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Opinions Mixed on Future for Lilly’s mGluR2/3 Agonist for Schizophrenia

6 August 2012. In a July 11 press release, Eli Lilly and Company announced that its metabotropic glutamate receptor agonist pomaglumetad methionil (also called LY2140023) has failed a Phase 2 clinical trial designed to evaluate its efficacy at improving positive and negative symptoms of patients with schizophrenia. Although the full data from this study—the third Phase 2 trial of monotherapy with this drug—are yet to be released, we do know enough to be disappointed: in contrast to the antipsychotic risperidone, the Lilly drug was no better than placebo at reducing symptoms.

The question of what this means for further research with mGluR2/3 drugs draws mixed responses from the schizophrenia research community. Some researchers wonder if the drug could still have positive effects in a subset of patients, or on a subset of symptoms. "Even if the primary endpoint didn’t meet criteria, you then go back and see if there are other symptoms that seem to have responded," said Daniel Javitt, of the Nathan Kline Institute.

In contrast, Bita Moghaddam of the University of Pittsburgh, whose animal experiments provided the initial rationale for the development of the drugs (Moghaddam and Adams, 1998), does not advocate for following up on direct mGluR2/3 receptor agonists as monotherapy, noting, “Once there are clinical data out there, you cannot argue with that.” She does, however, suggest there may be other ways to effect beneficial changes in glutamate neurotransmission in schizophrenia.

In this article, SRF looks back on the effort to develop a truly novel medication for schizophrenia, and asks some experts their opinions on the future of this enterprise.

The Great Glutamate Hope
Agonists of metabotropic glutamate receptor subtypes 2 and 3 have been on the schizophrenia stage for nearly 15 years, ever since Moghaddam’s 1998 study demonstrated that this class of drugs could reverse the cognitive deficits and psychosis induced by phencyclidine (PCP) exposure in an animal model. However, previous Phase 2 trials of the current drug have been mixed. The first extremely promising study reported a large reduction in symptoms after four weeks’ treatment with LY2140023 (a prodrug that is metabolized into the bioactive compound LY404039), assessed via Positive and Negative Symptom Scale (PANSS) change from baseline, an effect comparable to the antipsychotic olanzapine (see SRF related news story). However, in a second four-week trial, treatment with neither the mGluR2/3 agonist nor olanzapine was more effective than placebo at improving PANSS score. A greater-than-average placebo response was blamed for the lack of effect of both drugs, and thus, the second study was considered a wash (see SRF related news story; Kinon et al., 2011).

The current study, which began in early 2010 and concluded in May 2012, was similar to the design of the previous two, except that the drug was administered for seven weeks. Approximately 1,000 patients with an acute exacerbation of schizophrenia were given placebo, risperidone (2 mg twice daily), or LY2140023 (either 40 or 80 mg twice daily). Unfortunately, neither dose of the mGluR2/3 prodrug met the primary endpoint of the trial—a significant improvement in PANSS score over placebo—although risperidone did. The same was true regardless of whether all schizophrenia subjects were considered, or whether only a genetic subgroup (based on previous studies) was examined. LY2140023 was well tolerated and, importantly, no new safety information was reported.

The first two studies were consistent in terms of response to the Lilly drug. What differed was the response to placebo, providing hope that the previous failed study had been driven by the elevated placebo response. The expectation was that this third trial would replicate the original, bringing us one step closer to a rationally designed treatment for schizophrenia. But the current findings—that risperidone separated from placebo but LY2140023 did not—call into question the efficacy of the mGluR2/3 agonism mechanism, and may have put the problematic placebo hypothesis to rest.

The reaction of the community has been one of great disappointment. “This is obviously a discouraging finding,” said Yale University’s John Krystal. “And we all know that we have a tremendous need for the development of new medications for schizophrenia that target novel brain mechanisms.”

For Jeffrey Lieberman, of Columbia University, New York, the results were very surprising. “In many cases drugs fail … because of mistakes that are made on the part of the pharmaceutical industry or because of some kind of flaw in the development strategy. But this result comes about through no fault of Lilly,” he told SRF. “The theoretical rationale on which this compound was developed is very sound, and there were very strong preclinical data … indicating that it should be effective."

With one positive study, one inconclusive study, and now one failed study, the question is, Which one reflects reality? said Krystal. Of note, in the first study, patients on placebo actually got slightly worse across the trial, making the comparison to the mGluR2/3 drug look more favorable and raising concerns that the positive finding may have been “unrepresentative,” he added. In addition, Krystal said, the current data indicate that there’s a lot we still need to learn about the mechanism of the mGluR2/3 drug, and about the mGlu2 and mGlu3 receptors at which it acts. The two receptor subtypes have different functions, and thus, further basic science studies are needed to better understand the conflicting clinical data.

Hope springs pharmaceutical
In an e-mail, Lilly spokeswoman Keri McGrath told SRF, “We are disappointed by the results. However, Lilly's innovation strategy, which is based on advancing a pipeline of approximately 60 molecules currently in clinical development, does not rest on the success or failure of any single compound.” For now, Lilly says that they are pressing forward with the development of the mGluR2/3 agonist. A Phase 3 trial of the drug is ongoing, with results anticipated following its completion in February of 2013.

Although the current data on mGluR2/3 agonism as a monotherapy are not encouraging, it is possible the drug may work as an adjunct therapy to currently approved antipsychotics. In fact, preclinical data have suggested a synergism between these two classes of drugs (see SRF related news story). Lilly is currently awaiting results from a recently finished, long-term study (16 weeks) examining the efficacy of LY2140023 in addition to atypical antipsychotics in schizophrenia patients with prominent negative symptoms. Another possibility, says Krystal, is that the mGluR2/3 agonist may only be effective in a subgroup of patients, perhaps those who are early in their illness course, consistent with a clinical trial of another glutamate-enhancing drug, sarcosine (see SRF related news story).

Lilly is currently in the process of using a pharmacogenetics approach to identify subgroups of patients who may benefit from LY2140023. Thus far, 23 single nucleotide polymorphisms (SNPs), the majority of them located in the serotonin receptor 2a gene, have been significantly associated with mGluR2/3 agonist response to the PANSS (Liu et al., 2012). Presumably, it is these same SNPs that were used to define the genetic subgroup in the current study. However, the lack of mGluR2/3 agonist efficacy in this subpopulation of patients noted in the press release argues against this approach.

Javitt suggests that Lilly may need to keep searching to find the right indication for this compound. “There’s a lot invested in just demonstrating the safety of the compound, and it sounds like there were no safety issues. So then, often, what you try to do is look through the study to see where a signal is.” For example, one possibility is that LY2140023 may be more effective at improving cognitive deficits as opposed to positive and negative symptoms, consistent with early clinical data in healthy subjects demonstrating that mGluR2/3 agonists can improve working memory deficits induced by ketamine exposure (Krystal et al., 2005). However, it does not appear that the Phase 2 studies have made any cognitive measures, and thus, it will not be possible to address this issue with the current data.

Since efficacy with LY2140023 treatment was achieved in the acute study but not in the most recent one of longer duration, perhaps an allosteric site away from the main ligand binding site would be a better target. Moghaddam was not surprised at all by the current results, saying, "The initial data were from short-term exposure, and this being a direct agonist, it would be expected that this particular ligand … may not work for chronic exposure. Once the actual raw data are made available, if there’s something there early on that disappears, then we may still say that this particular receptor is a good target, but we need to go with allosteric modulation of it.”

Javitt also wonders if mGluR2/3 agonism may be better suited as a treatment for bipolar disorder, since increasing glutamate release through blockade of NMDA receptors produces hyperactivity in rats (Toth and Lajtha, 1986), perhaps for agitation or anxiety rather than psychosis.

The implications of this failed trial reach beyond schizophrenia, says Lieberman, and “reflect a difficulty in developing not just psychotropic drugs for mental disorders … but mechanistically novel drugs that may be trying to become first-in-class and forge a whole new therapeutic strategy.” Clearly, the animal models that we have for screening these compounds for efficacy have limitations, and once the data are released, says Javitt, it will be time to go back to basic science to see if we can use the present results to refine the models.—Allison A. Curley.

Comments on News and Primary Papers
Comment by:  Philip Seeman (Disclosure)
Submitted 15 August 2012
Posted 22 August 2012

The Lilly results of 11 July 2012 are not surprising, considering that the main ingredient of LY2140023 is LY404039, which is both a glutamate agonist and a weak partial dopamine agonist with only one-hundredth the potency of aripiprazole (Seeman and Guan, 2009; Seeman, 2012a), and considering that closer inspection of the clinical data (Kinon et al., 2011) showed that olanzapine was effective in schizophrenia, while LY2140023 was not (Seeman, 2012b).

References:

Kinon BJ, Zhang L, Millen BA, Osuntokun OO, Williams JE, Kollack-Walker S, Jackson K, Kryzhanovskaya L, Jarkova N, . A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol . 2011 Jun ; 31(3):349-55. Abstract

Seeman P, Guan HC. Glutamate agonist LY404,039 for treating schizophrenia has affinity for the dopamine D2(High) receptor. Synapse. 2009 Oct ; 63(10):935-9. Abstract

Seeman P. An agonist at glutamate and dopamine D2 receptors, LY404039. Neuropharmacology. 2012a Jul 4. Abstract

Seeman P. Comment on "A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia" by Kinon et al. J Clin Psychopharmacol. 2012b Apr ; 32(2):291-2; author reply 292-293. Abstract

View all comments by Philip SeemanComment by:  Hugo Geerts
Submitted 15 August 2012
Posted 22 August 2012

This is indeed another setback for the schizophrenia patient community, and it underscores the difficulty of translating animal model outcomes to the clinical situation. We have to think about introducing a new technology in schizophrenia drug discovery and development that would combine the best of preclinical animal information, but transplanted into a humanized environment to reverse this string of clinical failures.

One such approach is Quantitative Systems or Network Pharmacology, a computer-based mechanistic disease model of biophysically realistic neuronal networks that combines preclinical neurophysiology with human pathology, and clinical and imaging data (the topic of a recent NIH White Paper). Such an approach can be calibrated with retrospective clinical data, and then used to predict and examine future clinical trials. Applying this quantitative paradigm to the (also much publicized) failure of Dimebon in AD, researchers found that there was a fundamental off-target effect that precluded Dimebon from having cognitive benefits. Further analyses suggested that an imbalance in a common dopaminergic phenotype could increase part of the clinical signal difference as observed in the first (successful) Phase 2 trial.

In the case of schizophrenia, we find that affecting glutamatergic (such as with the mGluR2/R3 agonist) or GABA neurotransmission almost always leads to an inverse U-shaped dose response, because of the intrinsic balance between excitation and inhibition in cortical networks. Using such an approach forces discovery scientists to look beyond the single target and think about the impact on networks and circuits that ultimately drive human behavior and pathology in CNS disorders.

Unlike the traditional, currently used "cartoon"-based qualitative drawings, this approach allows for a quantitative outcome that, in principle, can help define the optimal "sweet spot" of the dose response by looking at the outcome of endophenotypes such as BOLD fMRI.

References:

Athan Spiros, Hugo Geerts. 2012. A quantitative way to estimate clinical off-target effects for human membrane brain targets in CNS Research and Development. Exp Pharmacology, 4; 53-61.

Athan Spiros, Patrick Roberts, Hugo Geerts. (2012) A Quantitative Systems Pharmacology Computer Model for Schizophrenia Efficacy and Extrapyramidal Side Effects, Drug Dev. Res, 73(4): 1098-1109.

View all comments by Hugo Geerts

Comments on Related News


Related News: Studies Explore Glutamate Receptors as Target for Schizophrenia Monotherapy

Comment by:  Dan Javitt, SRF Advisor
Submitted 3 September 2007
Posted 3 September 2007

A toast to success, or new wine in an old skin?
Patil et al. present a landmark study. It is the kind of study that represents the best of how science should work. It pulls together the numerous strands of schizophrenia research from the last 50 years, from the development of PCP psychosis as a model for schizophrenia in the late 1950s, through the links to glutamate, the discovery of metabotropic receptors, and the seminal discovery in 1998 by Moghaddam and Adams that metabotropic glutamate 2/3 receptor (mGluR2/3) agonists reverse the neurochemical and behavioral effects of PCP in rodents (Moghaddam and Adams, 1998. The story would not be possible without the elegant medicinal chemistry of Eli Lilly, which provided the compounds needed to test the theories; the research support of NIMH and NIDA, who have been consistent supporters of the “PCP theory”; or the hard work of academic investigators, who provided the theories and the platforms for testing. The study is large and the effects robust. Assuming they replicate (and there is no reason to suspect that they will not), this compound, and others like it, will represent the first rationally developed drugs for schizophrenia. Patients will benefit, drug companies will benefit, and academic investigators and NIH can feel that they have played their role in new treatment development.

Nevertheless, it is always the prerogative of the academic investigator to ask for more. In this case, we do not yet know if this will be a revolution in the treatment of schizophrenia, or merely a platform shift. What is striking about the study, aside from the effectiveness of LY2140023, is the extremely close parallel in both cross-sectional and temporal pattern of response between it and olanzapine. Both drugs change positive and negative symptoms in roughly equal proportions, despite their different pharmacological targets. Both drugs show approximately equal slopes over a 4-week period. There is no intrinsic reason why symptoms should require 4 or more weeks to resolve, or why negative and positive symptoms should change in roughly the same proportion with two medications from two such different categories, except that evidently they do.

There are many things about mGluR2/3 agonists that we do not yet know. The medication used here was administered at a single, fixed dose. It is possible that a higher dose might have been better, and that optimal results have not yet been achieved. The medications were used in parallel. It is possible that combined medication might be more effective than treatment with either class alone. The study was stopped at 4 weeks, with the trend lines still going down. It is possible that longer treatment duration in future studies might lead to even more marked improvement and that the LY and olanzapine lines might separate. No cognitive data are reported. It is possible that marked cognitive improvement will be observed with these compounds when cognition is finally tested, in which case a breakthrough in pharmacotherapy will clearly have been achieved.

If one were to look at the glass as half empty, then the question is why the metabotropic agonist did not beat olanzapine, and why the profiles of response were so similar. If these compounds work, as suggested in the article by modulating mesolimbic dopamine, then it is possible that metabotropic agonists will share the same therapeutic limitations as current antipsychotics—good drugs certainly and without the metabolic side effects of olanzapine, but not “cures.” The recent study with the glycine transport inhibitor sarcosine by Lane and colleagues showed roughly similar overall change in PANSS total (-17.1 pts) to that reported in this study, but larger change in negative symptoms (-5.5 pts), and less change in positive symptoms (-2.3 pts) in a similar type of patient population. Onset of effect in the sarcosine study also appeared somewhat faster. The sarcosine study was smaller (n = 20) and did not include a true placebo group. As with the Lilly study, it was only 4 weeks in duration, and did not include cognitive measures. It also included only two, possibly non-optimized doses. As medications become increasingly available to test a variety of mechanisms, side-by-side comparisons will become increasingly important.

There are also causes for concern and effects to be watched. For example, a side effect signal was observed for affect lability in the LY group, at about the same prevalence rate as weight increase in the olanzapine group. What this means for the mechanism and how this will effect treatment remains to be determined. Since these medications are agonists, there is concern that metabotropic receptors may downregulate over time. Thus, whether treatment effects increase, decrease, or remain constant over the course of long-term treatment will need to be determined. Nevertheless, 50 years since the near-contemporaneous discovery of both PCP and chlorpromazine, it appears that glutamatergic drugs for schizophrenia may finally be on the horizon.

References:

Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science. 1998 Aug 28;281(5381):1349-52. Abstract

View all comments by Dan Javitt

Related News: Studies Explore Glutamate Receptors as Target for Schizophrenia Monotherapy

Comment by:  Gulraj Grewal
Submitted 4 September 2007
Posted 4 September 2007
  I recommend the Primary Papers

Related News: Studies Explore Glutamate Receptors as Target for Schizophrenia Monotherapy

Comment by:  Shoreh Ershadi
Submitted 8 June 2008
Posted 9 June 2008
  I recommend the Primary Papers

Related News: ICOSR 2009—Unpleasing Placebos Cloud Antipsychotic Drug Trials

Comment by:  Paul Shepard
Submitted 23 April 2009
Posted 26 April 2009

When the 17 sites with high placebo responders were removed from the analysis, were only participants randomized to placebo removed or were all subjects who were recruited at these sites removed?

View all comments by Paul Shepard

Related News: ICOSR 2009—Unpleasing Placebos Cloud Antipsychotic Drug Trials

Comment by:  C. Anthony Altar
Submitted 28 April 2009
Posted 2 May 2009

Reply to P. Shepard
At ICOSR, Dr. Kinon presented the effects on PANSS positive values over 4 weeks for the placebo group, the groups receiving various LY2140023 doses, and those receiving olanzepine, but "without the 17 sites." I am reasonably sure, but not 100% positive, that this excluded all data from those sites, not just the placebo responders. Anything less would have introduced an unacceptable bias, even for a post-hoc analysis.

View all comments by C. Anthony Altar

Related News: ICOSR 2009—Unpleasing Placebos Cloud Antipsychotic Drug Trials

Comment by:  Ralph Hoffman
Submitted 19 May 2009
Posted 20 May 2009

These placebo results are certainly irksome, but may be important in positive ways. I am thinking of two hypotheses to account for these results. First, perhaps second-generation antipsychotic drugs (that are now more widely in use than ever) have more sustained therapeutic effects after discontinuation, so when patients are taken off their prescribed drugs to participate in these trials, their vulnerability to symptomatic worsening is less.

Of course, this would not explain the greater improvements in placebo groups. But perhaps with growing expectations regarding patient safety and support during randomized clinical trials overall, participants are getting more contact with research staff, which may have non-specific positive effects. We have, for instance, solid data indicating that significant social isolation is a trigger for psychotic symptoms independent of neuropsychological impairment in vulnerable individuals (unpublished data). The combination of reduced social isolation, increased staff support, plus (perhaps) sustained protective effects of second-generation drugs might account for emergence of greater positive placebo response.

View all comments by Ralph Hoffman

Related News: ICOSR 2011—Some Hope for Alleviating Negative Symptoms

Comment by:  Kimberly E. Vanover
Submitted 20 June 2011
Posted 20 June 2011

Thank you for your summary of the presentations from the New Drug Session at ICOSR 2011 on the Schizophrenia Research Forum. The Forum is a helpful and important resource.

I just wanted to clarify your description of ITI-007’s properties at the D2 site. As a dopamine phosphorylation modulator, ITI-007 acts as a pre-synaptic partial agonist and a post-synaptic antagonist with mesolimbic/mesocortical selectivity (Wennogle et al., 2008). In addition to its antagonism of 5-HT2A receptors and unique interaction with D2 receptors, it has affinity for D1 receptors, consistent with partial agonism linked to downstream increases in NMDA NR2B receptor phosphorylation (Zhu et al., 2008), and it is a serotonin reuptake inhibitor (Wennogle et al., 2008). Unfortunately, the short, 10-minute talk during the ICOSR session wasn’t sufficient time to go into the details of the mechanism and supporting preclinical data.

I did notice that a brief description for the mode of action for ITI-007 is listed as “5-HT2A antagonist + dopamine phosphoprotein modulator” with a role in schizophrenia listed as “DA stabilizer + 5hT-T inhibitor” in the Forum’s Drugs in Clinical Trials section. This is a nice, brief way to describe a rather complex mechanism.

References:

Wennogle LP, Snyder GL, Hendrick JP, Vanover KE, Tomesch JT, Li P, O’Callaghan JP, Miller DB, Fienberg AA, Davis RE, Mates S (2008) Unique antipsychotic profile of a novel 5-HT2A receptor antagonist and dopamine receptor protein phosphorylation modulator. Schizophrenia Research 98:Suppl1:15.

Zhu H, Snyder GL, Vanover KE, Rana M, Tsui T, Hendrick JP, Li P, Tomesch J, O’Brien JJ, Guo H, Davis RE, Fienberg AA, Wennogle LP, Mates S (2008) ITI-007: A novel 5-HT2A antagonist and dopamine protein phosphorylation modulator (DPPM) induces a distinct NR2B expression pattern in mouse brain. Program No. 155.14 2008 Neuroscience Meeting Planner. Washington, DC Society for Neuroscience, 2008. Online.

View all comments by Kimberly E. Vanover

Related News: SIRS 2014—Refining Schizophrenia Clinical Drug Trials

Comment by:  Anthony Grace, SRF Advisor (Disclosure)
Submitted 4 June 2014
Posted 4 June 2014

This was an important symposium, but I am concerned about the impression that these findings suggest a problem with translating data from animal models to the clinic. In order to translate effectively, one must use an animal model that recapitulates as much of the disease state as possible, and acute pharmacological challenges are inadequate for this. Developmental models should be a more effective screen. But perhaps more important, there is a very big difference between animal models and clinical trials: In animal models, the first therapeutic drug that the animal sees is the novel target compound. In contrast, clinical trials comprise patients that have been treated for antipsychotic drugs for decades, then withdrawn for only a single week before the test compound is evaluated.

It has been known for quite some time that repeated D2 antagonists change the brain in substantial ways. In our recent paper (Gill et al., 2014), we found that a GABAA alpha 5 compound that was highly effective in reversing dopamine neuron hyper-responsivity and amphetamine hyperlocomotion in MAM model rats was completely ineffective if the MAM rats were given just three weeks of haloperidol and withdrawn from the drug for one week. Therefore, once maintained on a D2 antipsychotic drug, we posit that the system changes from a hippocampal overdriven dopamine system to a postsynaptic dopamine receptor supersensitivity psychosis, such that only another D2 antagonist can now effectively replace the drug that had been withdrawn. We need to rethink clinical trial design if we are to effectively evaluate drugs with novel targets, or we may never get away from D2 antagonist therapy.

References:

Gill KM, Cook JM, Poe MM, Grace AA. Prior antipsychotic drug treatment prevents response to novel antipsychotic agent in the methylazoxymethanol acetate model of schizophrenia. Schizophr Bull. 2014 Mar ;40(2):341-50. Abstract

View all comments by Anthony Grace

Related News: Ketamine Elicits Brain State Resembling Early Stages of Schizophrenia

Comment by:  Hugo Geerts
Submitted 26 August 2014
Posted 26 August 2014

This is a very interesting contribution to improve the understanding of the progressive nature of schizophrenia pathology. Ketamine-induced effects have been used for a long time in healthy volunteers or in animal models, both rodents and non-human primates to "mimic" schizophrenia pathology. The observation that ketamine mimics more the very early schizophrenia or the at-risk state but not the more chronic pathology helps to explain the dissociation between effects of compounds in ketamine-induced deficits and in chronic schizophrenia, for example, nicotine (D'Souza et al., 2012), glycine transport inhibitor (D'Souza et al., 2012), haloperidol (Oranje et al., 2009), and lamotrigine (Goff et al., 2007).

The impact of these findings, if reproduced in a longitudinal study, is very important. This model of ketamine-induced deficit can be used in animals to test new experimental interventions in very early psychosis or in at-risk subjects. This is a patient group that is currently underserved in terms of therapeutic interventions and for which there is great interest. For the first time, we now have a model that mimics important aspects of the early schizophrenia pathology, and the hope is that when addressing these changes with the right medication early on, one could postpone or delay the onset of overt schizophrenia pathology, which could be the beginning of a preventive strategy.

References:

D'Souza DC, Ahn K, Bhakta S, Elander J, Singh N, Nadim H, Jatlow P, Suckow RF, Pittman B, Ranganathan M. Nicotine fails to attenuate ketamine-induced cognitive deficits and negative and positive symptoms in humans: implications for schizophrenia. Biol Psychiatry . 2012 Nov 1 ; 72(9):785-94. Abstract

D'Souza DC, Singh N, Elander J, Carbuto M, Pittman B, Udo De Haes J, Sjogren M, Peeters P, Ranganathan M, Schipper J. Glycine transporter inhibitor attenuates the psychotomimetic effects of ketamine in healthy males: preliminary evidence. Neuropsychopharmacology . 2012 Mar ; 37(4):1036-46. Abstract

Oranje B, Gispen-de Wied CC, Westenberg HG, Kemner C, Verbaten MN, Kahn RS. Haloperidol counteracts the ketamine-induced disruption of processing negativity, but not that of the P300 amplitude. Int J Neuropsychopharmacol . 2009 Jul ; 12(6):823-32. Abstract

Goff DC, Keefe R, Citrome L, Davy K, Krystal JH, Large C, Thompson TR, Volavka J, Webster EL. Lamotrigine as add-on therapy in schizophrenia: results of 2 placebo-controlled trials. J Clin Psychopharmacol . 2007 Dec ; 27(6):582-9. Abstract

View all comments by Hugo Geerts

Related News: Ketamine Elicits Brain State Resembling Early Stages of Schizophrenia

Comment by:  Alexandre Seillier
Submitted 9 September 2014
Posted 11 September 2014

The "Ketamine Model" Revived?
Despite the seminal review by Jentsch and Roth arguing that long-term, rather than acute administration of NMDA antagonists, such as phencyclidine (PCP) and ketamine, may more isomorphically model schizophrenia (Jentsch and Roth, 1999), acute ketamine remained one of the most widely utilized pharmacological models in both humans and rodents. Recently, Dawson and co-workers added to the accumulating body of evidence that "alterations in brain circuitry that result from chronic, but not from acute, NMDA receptor blockade most accurately reflect the systems level differences in brain network functioning seen in schizophrenia" (Dawson et al., 2014a; Dawson et al., 2014b). Indeed, using brain network connectivity, they reported that, "at a systems level, the mechanisms through which acute ketamine treatment induces schizophrenia-like symptoms may be profoundly divergent from those that contribute to these symptoms in the disorder."

This new study by Anticevic et al. (2014) might have resolved the paradox of acute ketamine-induced hyperfrontality given the hypofrontality observed in schizophrenia. As previously shown in both healthy humans and mice (Dawson et al., 2014a; Driesen et al., 2013), acute ketamine administration was associated with increased prefrontal cortex connectivity. On the other hand, whereas chronic schizophrenics had reduced prefrontal cortex functional connectivity, patients in the early stage of schizophrenia showed increased prefrontal cortex functional connectivity. As stated by the authors, "these data point to a qualitative difference between NMDAR antagonist and chronic schizophrenia effects, suggesting that ketamine's effect on prefrontal cortex connectivity may be more relevant to particular illness stages."

Longitudinal studies will be necessary to confirm that the "phase of illness is an important moderator of the prefrontal cortex functional connectivity in schizophrenia." The authors also addressed some discrepancies that need to be highlighted. First, the reduced and the increased prefrontal cortex functional connectivity in chronic versus early-stage schizophrenia, respectively, were observed in distinct prefrontal areas, namely the right middle frontal gyrus and the left superior frontal gyrus, respectively. Second, the cross-validation of the pharmacological and clinical analysis failed to reach significance; i.e., acute ketamine did not significantly change connectivity in the regions identified in the clinical study. Although it has limitations, this study should inform the application of acute ketamine as a translational model that may better approximate some early stage of schizophrenia.

References:

Dawson N, McDonald M, Higham DJ, Morris BJ, Pratt JA (2014a) Subanesthetic Ketamine Treatment Promotes Abnormal Interactions between Neural Subsystems and Alters the Properties of Functional Brain Networks. Neuropsychopharmacology 39:1786-98. Abstract

Dawson N, Xiao X, McDonald M, Higham DJ, Morris BJ, Pratt JA (2014b) Sustained NMDA receptor hypofunction induces compromised neural systems integration and schizophrenia-like alterations in functional brain networks. Cereb Cortex 24: 452-464. Abstract

Driesen NR, McCarthy G, Bhagwagar Z, Bloch M, Calhoun V, D'Souza DC et al (2013) Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine. Mol Psychiatry 18:1199-1204. Abstract

Jentsch JD, Roth RH (1999) The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology 20: 201-225. Abstract

View all comments by Alexandre Seillier

Related News: Ketamine Elicits Brain State Resembling Early Stages of Schizophrenia

Comment by:  Albert Adell
Submitted 10 September 2014
Posted 16 September 2014

The paper by Anticevic and co-workers, as well as the commentary by Hugo Geerts, points to a very interesting issue on the similitude of the ketamine model with schizophrenia. In a previous mini-review, we anticipated that it would be conceivable that acute administration of NMDA receptor antagonists would lead to a reversible malfunctioning of PV-containing interneurons, whereas in schizophrenia, a damage of these neurons may take place at early stages of neurodevelopment (Adell et al., 2012). In summary, acute NMDA antagonism would resemble the early stage of schizophrenia, whereas chronic exposure better models the more chronic pathology of the illness.

References:

Adell A, Jiminez-Sanchez L, Lopez-Gil X, Roman T. Is the Acute NMDA Receptor Hypofunction a Valid Model of Schizophrenia? Schizophr Bull 38(1): 9-14. Abstract

View all comments by Albert Adell

Related News: Ketamine Elicits Brain State Resembling Early Stages of Schizophrenia

Comment by:  Didier Pinault
Submitted 25 September 2014
Posted 26 September 2014

Acute Ketamine Dramatically Amplifies Network Gamma (30-80 Hz) and Higher-Frequency Oscillations
N-methyl D-aspartate receptors play a key role in synaptic plasticity, memory processes, and in the modulation of field oscillations. The non-competitive NMDAR antagonist ketamine has context-dependent and dose-dependent multiple properties, including positive and negative effects. For instance, a single sub-anesthetic administration can disturb cognitive and perceptual processes and induce schizophreniform psychosis in healthy subjects (Krystal et al., 1994; Adler et al., 1998; Newcomer et al., 1999; Hetem et al., 2000); puzzlingly, but of importance, ketamine can generate a durable antidepressant effect in patients refractory to conventional antidepressant therapies (Zarate et al., 2006; Fond et al., 2014; McGirr et al., 2014).

More specifically, Anticevic and colleagues (2014), using brain scans, recently revealed that a single sub-anesthetic administration of ketamine in healthy subjects at rest produces in the prefrontal cortex a state of hyperconnectivity, which resembles that recorded in people in the early stages of schizophrenia but not in patients with chronic (several years' duration) schizophrenia. Also, using fMRI in healthy human subjects, Driesen and colleagues (Driesen et al., 2013) demonstrated that the NMDA receptor antagonist ketamine increases global brain functional connectivity and reduces negative symptoms, suggesting that the ketamine-induced increase in connectivity corresponds to a state of enhanced cortical function. The acute ketamine effects appear quickly (~1-2 minutes) and are transient. In the following, we will see that these fresh clinical findings are consistent with preclinical studies demonstrating that, in rodents, non-competitive NMDAR antagonists increase the amount of field (or network) gamma frequency oscillations (GFOs; 30-80 Hz) in cortical and subcortical regions. In healthy human subjects, ketamine increases the power of GFOs and decreases that of delta oscillations during auditory-evoked network oscillations (Hong et al., 2010).

What does "hyperconnectivity" mean? From clinical imaging studies, functional connectivity is assessed by the degree of correlation between pairwise functional connections from multiple functional cortical and subcortical regions. What does it mean in terms of neural excitatory and inhibitory activities, network oscillations, and cellular firing?

In rodents a single sub-anesthetic administration of ketamine quickly and transiently induces abnormal behavior (hyperlocomotion, ataxia), memory deficits, and abnormally persistent and generalized hypersynchronized (200-400 percent increased power) ongoing GFOs (Ma and Leung, 2007; Chrobak et al., 2008; Pinault, 2008; Hakami et al., 2009; Ehrlichman et al., 2009; Kocsis, 2012). The gamma frequency at maximal power is significantly increased by approximately 10 Hz on average (Pinault, 2008). The amount of ongoing higher-frequency (>80 Hz) oscillations is also increased following a single sub-anesthetic administration (<10 mg/kg) of ketamine (Hakami et al., 2009; Hunt et al., 2006; Kulikova et al., 2012).

In addition, NMDAR antagonists transiently disrupt the expression, not the induction, of long-term potentiation in the thalamocortical system (Kulikova et al., 2012), disorganize action potential firing in rat prefrontal cortex (Molina et al., 2014), increase the firing in fast-spiking neurons, and decrease that in regularly spiking neurons (Homayoun and Moghaddam, 2007). These results suggest that the amount of ongoing GFOs is inversely related to synaptic potentiation in the thalamocortical system (Kulikova et al., 2012). They also suggest that the ketamine-induced state results in part from dysfunction of cortical GABAergic interneurons that would lead to hyperexcitation of projection glutamatergic neurons and to glutamate release (Homayoun and Moghaddam, 2007).

Following the subcutaneous administration of a low dose (<10 mg/kg) of ketamine, both the duration and the amplitude of spontaneously occurring GFOs significantly increase in the rat frontal, parietal, and occipital cortices (Pinault, 2008; Hakami et al., 2009). From a mathematical viewpoint (Cadonic and Albensi, 2014), it was proposed that natural, physiological ongoing GFOs operate like damped harmonic oscillators, which would leave room for synaptic potentiation, learning, and memory, whereas ketamine-induced persistently amplified GFOs run like forced harmonic oscillators, which would disrupt the network ability in information processing and reduce the expression of synaptic potentiation (Pinault, 2014). This might be a key neurophysiological substrate of the functional hyperconnectivity observed by Anticevic and colleagues (2014) and by Driesen and colleagues (Driesen et al., 2013).

There is a growing body of evidence suggesting that the NMDAR antagonist ketamine modulates not only GFOs and higher-frequency oscillations, as mentioned above, but also lower-frequency oscillations, including alpha, theta, and delta oscillations (Ehrlichman et al., 2009; Hong et al., 2010; Palenicek et al., 2011; Tsuda et al., 2007). This broad-spectrum effect depends on the injected dose, the experimental and recording conditions, and on the anatomo-functional properties of the structures under investigation. For instance, under in vivo conditions, a single low-dose (<10 mg/kg) ketamine administration alters specifically GFOs and higher-frequency oscillations (Pinault, 2008; Hakami et al., 2009; Ma and Leung, 2007), while higher doses in addition affect slower rhythms (Ehrlichman et al., 2009; Hunt et al., 2006; Palenicek et al., 2011; Caixeta et al., 2013; Hiyoshi et al., 2014; Nicolas et al., 2011; Buzsaki, 1991). Therefore, we must be prudent when comparing results and inferring mechanisms from studies using different doses of NMDAR antagonists and various and diverse animal and network models. This is fundamental for basic-clinical translational understanding.

Investigating the pathophysiology of schizophrenia in relation to "noise and signal-to-noise ratio" is an appealing basic-clinical translational way to understand the neural mechanisms underlying the multiple symptoms that characterize this complex and heterogeneous neurobiological disease (Rolls et al., 2008). I recently argued on the notion of network signal-to-noise ratio (Pinault, 2014). In any system, both the amount of the ongoing (background or baseline) activity and the amplitude (or power) of its global response to the activation of its inputs are indicators of its state and functionality. The possible noise-signal interplay(s) might in part explain some disparities between findings (e.g., increases and decreases in GFOs in patients with schizophrenia; see SRF Live Discussion organized by Peter Uhlhaas and Kevin Spencer).

More precisely, in the rat thalamocortical system, ketamine simultaneously increases the power of spontaneously occurring GFOs (signature of a change in the state of the system) and decreases sensory-evoked GFOs (signature of a disturbance of the functionality of the system) (Pinault, 2008; Hakami et al., 2009; Kulikova et al., 2012). Assuming that sensory-evoked GFOs include a "true" sensory-related component, the ketamine-induced gamma noise amplification decreases the ability of the thalamocortical system to discriminate the sensory-evoked gamma signal drowned in the noise. In other words, the NMDAR antagonist ketamine decreases the gamma signal-to-noise ratio during sensory information processing. Such a ratio may be considered as a suitable neurophysiological marker of neural networks to evaluate their function and dysfunction.

This dramatically excessive ongoing gamma noise, which might be involved in the ketamine-induced state of hyperconnectivity in healthy subjects (Anticevic et al., 2014; Driesen et al., 2013), is thought to affect global brain state and operation, and to contribute to psychosis. Moreover, continuous and stereotyped GFOs might be responsible for clinical positive symptoms (Llinas et al., 1999). Furthermore, ongoing abnormally hypersynchronized GFOs have been recorded in patients experiencing sensory hallucinations (Baldeweg et al., 1998; Behrendt, 2003; Spencer et al., 2004; Ffytche, 2008; Becker et al., 2009). Hypersynchronized GFOs in cortico-thalamo-cortical systems are thought to play a key role during the appearance of hallucinations (Baldeweg et al., 1998; Behrendt, 2003), raising the question as to whether persistent amplification of ongoing GFOs could somehow conceal function-related GFOs in the corresponding brain networks.

References

Adler CM, Goldberg TE, Malhotra AK, Pickar D, Breier A (1998) Effects of Ketamine on Thought Disorder, Working Memory, and Semantic Memory in Healthy Volunteers. Biological Psychiatry 43:811-816. Abstract

Baldeweg T, Spence S, Hirsch SR, Gruzelier J (1998) Gamma-band electroencephalographic oscillations in a patient with somatic hallucinations. Lancet 352:620-621. Abstract

Becker C, Gramann K, Muller HJ, Elliott MA (2009) Electrophysiological correlates of flicker-induced color hallucinations. Conscious Cogn 18:266-276. Abstract

Behrendt RP (2003) Hallucinations: synchronisation of thalamocortical gamma oscillations underconstrained by sensory input. Conscious Cogn 12:413-451. Abstract

Buzsaki G (1991) The thalamic clock: emergent network properties. Neuroscience 41:351-364. Abstract

Cadonic C, Albensi BC (2014) Oscillations and NMDA receptors: Their interplay create memories. AIMS Neuroscience 1:52-64.

Caixeta FV, Cornelio AM, Scheffer-Teixeira R, Ribeiro S, Tort AB (2013) Ketamine alters oscillatory coupling in the hippocampus. Sci Rep 3:2348. Abstract

Chrobak JJ, Hinman JR, Sabolek HR (2008) Revealing past memories: proactive interference and ketamine-induced memory deficits. J Neurosci 28:4512-4520. Abstract

Driesen NR, McCarthy G, Bhagwagar Z, Bloch M, Calhoun V, D'souza DC, Gueorguieva R, He G, Ramachandran R, Suckow RF, Anticevic A, Morgan PT, Krystal JH (2013) Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans. Mol Psychiatry 18:1199-1204. Abstract

Ehrlichman RS, Gandal MJ, Maxwell CR, Lazarewicz MT, Finkel LH, Contreras D, Turetsky BI, Siegel SJ (2009) N-methyl-d-aspartic acid receptor antagonist-induced frequency oscillations in mice recreate pattern of electrophysiological deficits in schizophrenia. Neuroscience 158:705-712. Abstract

Ffytche DH (2008) The hodology of hallucinations. Cortex 44:1067-1083. Abstract

Fond G, Loundou A, Rabu C, Macgregor A, Lancon C, Brittner M, Micoulaud-Franchi JA, Richieri R, Courtet P, Abbar M, Roger M, Leboyer M, Boyer L (2014) Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology (Berl) 231: 3663-3676. Abstract

Hakami T, Jones NC, Tolmacheva EA, Gaudias J, Chaumont J, Salzberg M, O'Brien TJ, Pinault D (2009) NMDA receptor hypofunction leads to generalized and persistent aberrant gamma oscillations independent of hyperlocomotion and the state of consciousness. PLoS One 4:e6755. Abstract

Hetem LA, Danion JM, Diemunsch P, Brandt C (2000) Effect of a sub-anesthetic dose of ketamine on memory and conscious awareness in healthy volunteers. Psychopharmacology (Berl) 152:283-288. Abstract

Hiyoshi T, Kambe D, Karasawa J, Chaki S (2014) Differential effects of NMDA receptor antagonists at lower and higher doses on basal gamma band oscillation power in rat cortical electroencephalograms. Neuropharmacology 85:384-396. Abstract

Homayoun H, Moghaddam B (2007) NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci 27:11496-11500. Abstract

Hong LE, Summerfelt A, Buchanan RW, O'Donnell P, Thaker GK, Weiler MA, Lahti AC (2010) Gamma and delta neural oscillations and association with clinical symptoms under subanesthetic ketamine. Neuropsychopharmacology 35:632-640. Abstract

Hunt MJ, Raynaud B, Garcia R (2006) Ketamine dose-dependently induces high-frequency oscillations in the nucleus accumbens in freely moving rats. Biol Psychiatry 60:1206-1214. Abstract

Kocsis B (2012) Differential role of NR2A and NR2B subunits in N-methyl-D-aspartate receptor antagonist-induced aberrant cortical gamma oscillations. Biol Psychiatry 71:987-995. Abstract

Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB, Jr., Charney DS (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199-214. Abstract

Kulikova SP, Tolmacheva EA, Anderson P, Gaudias J, Adams BE, Zheng T, Pinault D (2012) Opposite effects of ketamine and deep brain stimulation on rat thalamocortical information processing. Eur J Neurosci 36:3407-3419. Abstract

Llinas RR, Ribary U, Jeanmonod D, Kronberg E, Mitra PP (1999) Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography. Proc Natl Acad Sci U S A 96:15222-15227. Abstract

Ma J, Leung LS (2007) The supramammillo-septal-hippocampal pathway mediates sensorimotor gating impairment and hyperlocomotion induced by MK-801 and ketamine in rats. Psychopharmacology (Berl) 191:961-974. Abstract

McGirr A, Berlim MT, Bond DJ, Fleck MP, Yatham LN, Lam RW (2014) A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med1-12. Abstract

Molina LA, Skelin I, Gruber AJ (2014) Acute NMDA receptor antagonism disrupts synchronization of action potential firing in rat prefrontal cortex. PLoS One 9:e85842. Abstract

Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, Craft S, Olney JW (1999) Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology 20:106-118. Abstract

Nicolas MJ, Lopez-Azcarate J, Valencia M, Alegre M, Perez-Alcazar M, Iriarte J, Artieda J (2011) Ketamine-induced oscillations in the motor circuit of the rat basal ganglia. PLoS One 6:e21814. Abstract

Palenicek T, Fujakova M, Brunovsky M, Balikova M, Horacek J, Gorman I, Tyls F, Tislerova B, Sos P, Bubenikova-Valesova V, Hoschl C, Krajca V (2011) Electroencephalographic spectral and coherence analysis of ketamine in rats: correlation with behavioral effects and pharmacokinetics. Neuropsychobiology 63:202-218. Abstract

Pinault D (2008) N-methyl d-aspartate receptor antagonists ketamine and MK-801 induce wake-related aberrant gamma oscillations in the rat neocortex. Biol Psychiatry 63:730-735. Abstract

Pinault (2014) N-methyl D-aspartate receptor antagonists amplify network baseline gamma frequency (30-80 Hz) oscillations: Noise and signal. AIMS Neuroscience 1:169-182.

Rolls ET, Loh M, Deco G, Winterer G (2008) Computational models of schizophrenia and dopamine modulation in the prefrontal cortex. Nat Rev Neurosci 9:696-709. Abstract

Spencer KM, Nestor PG, Perlmutter R, Niznikiewicz MA, Klump MC, Frumin M, Shenton ME, McCarley RW. Neural synchrony indexes disordered perception and cognition in schizophrenia. Proc Natl Acad Sci U S A . 2004 Dec 7 ; 101(49):17288-93. Abstract

Tsuda N, Hayashi K, Hagihira S, Sawa T (2007) Ketamine, an NMDA-antagonist, increases the oscillatory frequencies of alpha-peaks on the electroencephalographic power spectrum. Acta Anaesthesiol Scand 51:472-481. Abstract

Zarate CA, Jr., Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK (2006) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856-864. Abstract

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Related News: Ketamine Elicits Brain State Resembling Early Stages of Schizophrenia

Comment by:  Alan AnticevicJohn Krystal (SRF Advisor)
Submitted 8 October 2014
Posted 8 October 2014

Linking Hyperconnectivity Induced via Acute Ketamine to Neuronal Mechanisms and Emerging System-Level Markers in Schizophrenia
We sincerely appreciate the recent engaging commentaries focusing on our paper. The constructive and thoughtful discussion has raised a number of important issues regarding the ketamine model in schizophrenia research. In particular, in the latest commentary Dr. Pinault has noted several hypotheses regarding our findings on which we would like to further comment.

First, what does the observed "hyperconnectivity" represent functionally? Does this "signature" relate to alterations in excitation (E) and inhibition (I) balance in cortical circuits and in turn reflect an elevation in shared signal between prefrontal areas in our analyses? It is important to note that the reported effect builds on basic preclinical studies and studies examining cortical metabolism, which have established that NMDAR antagonism elevates pyramidal cell activity (Moghaddam and Adams, 1998), extracellular glutamate levels (Homayoun and Moghaddam, 2007), cortical metabolism (Breier et al., 1997; Lahti et al., 1995; Lahti et al., 2001; Vollenweider et al., 1997; Vollenweider et al., 2000), and resting-state functional connectivity (Driesen et al., 2013; Pinault, 2008; Driesen et al., 2013). Moreover, a recent influential study by Schobel and colleagues demonstrated that NMDAR antagonism caused elevated "spreading" of hippocampal activation and metabolism (Schobel et al., 2013). Strikingly, they showed that repeated NMDAR antagonist dosing eventually caused chronic hippocampal atrophy, resembling observations after longer periods of illness. A possible corollary of this preclinical finding suggests that aberrant increases in excitation, and perhaps connectivity induced by NMDAR antagonism, are likely pathological. Therefore, the "hyperconnectivity" pattern may reflect increased pyramidal cell excitability, reduced pyramidal input selectivity, or other sources of aberrant cortical hypersynchrony.

One mechanism could involve reductions in the inhibitory component of cortical connectivity, which may alter excitatory connections. It is possible that such deficits not only increase excitability, but also reduce the input selectivity of cortical excitation (i.e., pathologically increase cortical functional connectivity). It will be critical for future studies to establish whether the observed "hyperconnectivity" measured via BOLD fMRI also relates to concurrently abnormal oscillations measured via EEG and in what frequency band. We comment on this specific issue below. Relatedly, follow-up clinical and pharmacological investigations should more carefully decompose the "correlation" measures between pairwise regions by considering both shared and unshared signal components (Friston, 2011). Put differently, it will be critical to show that the alterations in BOLD functional connectivity measures actually reflect elevations in aberrant shared signal (not just alterations in the variance structure), which could also be altered in schizophrenia (Yang et al., 2014). Pinpointing the precise nature of signal alteration that induces "hyperconnectivity" will have key implications for interpreting this effect and, in turn, for treatment studies designed to reverse this effect.

Second, what might be the precise synaptic contributions to such aberrant "hyperconnectivity"? Dr. Pinault elegantly argues for the role of GABAergic interneurons in the reported effect. We are in full agreement here; a number of studies have implicated interneurons as playing a key role in the effects of NMDAR antagonists (Krystal and Moghaddam, 2011; Krystal et al., 1994; Krystal et al., 2003; Anticevic et al., 2012). It remains unknown, however, which interneuron subtype is predominantly involved in their effects. We posit that the combination of preclinical animal work and computational modeling approaches is well positioned to address this question. For instance, studies that carefully experimentally dissect the potential contributions of specific neuronal subtypes to the observed "hyperconnectivity" pattern will be important to constrain our mechanistic understanding of acute NMDAR antagonist effects on cortical microcircuits (Kwan and Dan, 2012). Similarly, computational studies that incorporate multiple interneuron subtypes will help generate predictions for both electrophysiological and functional connectivity experiments that can be tested in animals and humans (Lisman et al., 2010; Lisman, 2012). It is well established that there are two broad classes of interneurons—fast-spiking cells that are critical for gamma oscillations and slower-spiking cells that strongly contribute to theta oscillations (Lisman, 2012). As noted, it remains unknown which GABAergic interneuron contribution "drives" the hyperconnectivity and at which frequency band (i.e., gamma or theta). It is demonstrated that systemic ketamine administration attenuates theta power but concurrently increases gamma power in mice (Ehrlichman et al., 2009; Lazarewicz et al., 2010), rats (Sabolek, H., et al., 2006), and humans (Hong et al., 2010). Computational simulations established that manipulating NMDAR currents on slow-spiking GABAergic cells (as opposed to fast-spiking cells) captured these dissociable gamma/theta experimental observations in silico (Neymotin et al., 2011). Forthcoming computational studies should strive to extend such micro-circuit models to capture neural system-level connectivity alterations in schizophrenia and following pharmacological challenge (Anticevic et al., 2013). In turn, these computational models can generate cell-specific predictions for NMDAR antagonist effects that can be tested experimentally, both preclinically and in human neuroimaging studies (Kwan and Dan, 2012).

Third, is there a dose effect of acute NMDAR antagonists? We believe that there might be a dose effect, which needs to be carefully considered when interpreting present effects—as argued by Dr. Pinault. Perhaps cognitive activation studies can speak to this issue. For instance, in a recent related study, we found that acute NMDAR antagonism in humans reduced cognitive performance—namely delayed spatial working memory (WM) by preferentially increasing error rates to non-target probes at specific spatial locations that were proximal to original WM locations (Murray et al., 2014). Put differently, volunteers administered ketamine were more likely to report a false alarm than report a memory at a location that they had not previously seen (a miss). We qualitatively and quantitatively captured this effect in our computational model by mildly reducing NMDAR drive onto inhibitory cells in the model—effectively inducing disinhibition and a "blurring" of the WM representation (Murray et al., 2014). The model performance mimicked that of healthy human volunteers at low levels of NMDAR antagonism but not at higher levels, where recurrent excitation on pyramidal cells was also reduced (Wang et al., 2013).

In a related animal study, Arnsten and colleagues examined effects of acute ketamine administration in monkeys during performance of a similar delayed spatial WM task (Wang et al., 2013). In their experiment the animals produced random saccades at previously unseen probe locations (i.e., misses), suggesting a complete loss of memory representation, accompanied by reduced delay-related firing of prefrontal neurons. In our computational simulations we were able to capture both behavioral results as reflecting distinct levels of NMDAR antagonism. In that sense, it may be the case that distinct dose-dependent levels of NMDAR antagonism produce different E/I balance regimes. Put differently, at higher doses of ketamine, where both the inhibitory and excitatory NMDAR synaptic components are affected, the "hyperconnectivity" regime may be replaced by functional connectivity reductions—a hypothesis that needs systematic experimental testing in animals. Therefore, we argue for the importance of carefully dissecting the dose-dependent contributions of ketamine on both behavior and functional connectivity in humans.

Fourth, how might the prefrontal "hyperconnectivity" effect relate to emerging "thalamo-cortical" markers of schizophrenia? An excellent observation in Dr. Pinault's commentary raises the importance of linking the observed "hyperconnectivity," which may possibly reflect alterations in gamma-band oscillations, to the thalamo-cortical gating abnormalities that underlie many theoretical models of schizophrenia (Andreasen, 1997). Unifying these effects constitutes an important theoretical and experimental goal in light of several recent empirical reports showing elevated sensory-thalamic functional connectivity in chronic schizophrenia patients (Woodward et al., 2012; Klingner et al., 2014; Anticevic et al., 2013). It may be the case that NMDAR antagonism "elevates" this sensory-thalamic coupling, either by decreasing the gamma signal-to-noise ratio or possibly by affecting the prefrontal "top-down" control aspect of sensory-thalamic information flow. These scenarios remain to be systematically tested.

In addition, it will be important to establish whether the thalamo-cortical disconnectivity in schizophrenia also exhibits functional dissociations along illness stages or appears during initial illness onset, as reported here for prefrontal hyperconnectivity. In that sense, some neural markers may show "dynamic" change along illness stages or perhaps reflect state-dependent functional causes (e.g., transient symptom exacerbation), whereas other functional connectivity markers may reflect a "trait-like" signature that persists across the illness course. Further establishing how the ketamine model maps onto these distinct neural signatures across illness stages and functional states represents a key goal for harnessing the ketamine model for targeted drug development for schizophrenia.

References
Moghaddam B, Adams BW. Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science. 1998 Aug 28;281(5381):1349-52. Abstract

Homayoun H, Moghaddam B. NMDA receptor hypofunction produces opposite effects on prefrontal cortex interneurons and pyramidal neurons. J Neurosci. 2007 Oct 24;27(43):11496-500. Abstract

Breier A, Malhotra AK, Pinals DA, Weisenfeld NI, Pickar D. Association of ketamine-induced psychosis with focal activation of the prefrontal cortex in healthy volunteers. Am J Psychiatry. 1997 Jun;154(6):805-11. Abstract

Lahti AC, Holcomb HH, Medoff DR, Tamminga CA. Ketamine activates psychosis and alters limbic blood flow in schizophrenia. Neuroreport. 1995 Apr 19;6(6):869-72. Abstract

Lahti AC, Holcomb HH, Medoff DR, Weiler MA, Tamminga CA, Carpenter WT. Abnormal patterns of regional cerebral blood flow in schizophrenia with primary negative symptoms during an effortful auditory recognition task. Am J Psychiatry. 2001 Nov;158(11):1797-808. Abstract

Vollenweider FX, Leenders KL, Scharfetter C, Antonini A, Maguire P, Missimer J, Angst J. Metabolic hyperfrontality and psychopathology in the ketamine model of psychosis using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG). Eur Neuropsychopharmacol. 1997 Feb;7(1):9-24. Abstract

Vollenweider FX, Vontobel P, Oye I, Hell D, Leenders KL. Effects of (S)-ketamine on striatal dopamine:a [11C]raclopride PET study of a model psychosis in humans. J Psychiatr Res. 2000 Jan-Feb;34(1):35-43. Abstract

Driesen NR, McCarthy G, Bhagwagar Z, Bloch M, Calhoun V, D'Souza DC, Gueorguieva R, He G, Ramachandran R, Suckow RF, Anticevic A, Morgan PT, Krystal JH. Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans. Mol Psychiatry. 2013 Nov;18(11):1199-204. Abstract

Pinault D. N-methyl d-aspartate receptor antagonists ketamine and MK-801 induce wake-related aberrant gamma oscillations in the rat neocortex. Biol Psychiatry. 2008 Apr 15;63(8):730-5. Abstract

Driesen NR, McCarthy G, Bhagwagar Z, Bloch MH, Calhoun VD, D'Souza DC, Gueorguieva R, He G, Leung HC, Ramani R, Anticevic A, Suckow RF, Morgan PT, Krystal JH. The impact of NMDA receptor blockade on human working memory-related prefrontal function and connectivity. Neuropsychopharmacology. 2013 Dec;38(13):2613-22. Abstract

Schobel SA, Chaudhury NH, Khan UA, Paniagua B, Styner MA, Asllani I, Inbar BP, Corcoran CM, Lieberman JA, Moore H, Small SA. Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron. 2013 Apr 10;78(1):81-93. Abstract

Friston KJ. Functional and effective connectivity:a review. Brain Connect. 2011;1(1):13-36. Abstract

Yang GJ, Murray JD, Repovs G, Cole MW, Savic A, Glasser MF, Pittenger C, Krystal JH, Wang XJ, Pearlson GD, Glahn DC, Anticevic A. Altered global brain signal in schizophrenia. Proc Natl Acad Sci U S A. 2014 May 20;111(20):7438-43. Abstract

Krystal, J.H. and B. Moghaddam, Contributions of glutamate and GABA systems to the neurobiology and treatment of schizophrenia., in Schizophrenia, 3nd edition, P.J. Weinberger and P.J. Harrison, Editors. 2011, Blackwell Science:Oxford. p. 433-461.

Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB, Charney DS. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994 Mar;51(3):199-214. Abstract

Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R. NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia:toward a paradigm shift in medication development. Psychopharmacology (Berl). 2003 Sep;169(3-4):215-33.Abstract

Anticevic A, Gancsos M, Murray JD, Repovs G, Driesen NR, Ennis DJ, Niciu MJ, Morgan PT, Surti TS, Bloch MH, Ramani R, Smith MA, Wang XJ, Krystal JH, Corlett PR. NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia. Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16720-5. Abstract

Kwan AC, Dan Y. Dissection of cortical microcircuits by single-neuron stimulation in vivo. Curr Biol. 2012 Aug 21;22(16):1459-67. Abstract

Lisman JE, Pi HJ, Zhang Y, Otmakhova NA. A thalamo-hippocampal-ventral tegmental area loop may produce the positive feedback that underlies the psychotic break in schizophrenia. Biol Psychiatry. 2010 Jul 1;68(1):17-24. Abstract

Lisman J. Excitation, inhibition, local oscillations, or large-scale loops:what causes the symptoms of schizophrenia? Curr Opin Neurobiol. 2012 Jun;22(3):537-44. Abstract

Ehrlichman RS, Gandal MJ, Maxwell CR, Lazarewicz MT, Finkel LH, Contreras D, Turetsky BI, Siegel SJ. N-methyl-d-aspartic acid receptor antagonist-induced frequency oscillations in mice recreate pattern of electrophysiological deficits in schizophrenia. Neuroscience. 2009 Jan 23;158(2):705-12. Abstract

Lazarewicz MT, Ehrlichman RS, Maxwell CR, Gandal MJ, Finkel LH, Siegel SJ. Ketamine modulates theta and gamma oscillations. J Cogn Neurosci. 2010 Jul;22(7):1452-64. Abstract

Sabolek, H., et al., Ketamine alters synchrony throughout the hippocampal formation. Society for Neuroscience, 2006. 32:751.12.

Hong LE, Summerfelt A, Buchanan RW, O'Donnell P, Thaker GK, Weiler MA, Lahti AC. Gamma and delta neural oscillations and association with clinical symptoms under subanesthetic ketamine. Neuropsychopharmacology. 2010 Feb;35(3):632-40. Abstract

Neymotin SA, Lazarewicz MT, Sherif M, Contreras D, Finkel LH, Lytton WW. Ketamine disrupts modulation of in a computer model of hippocampus. J Neurosci. 2011 Aug 10;31(32):11733-43. Abstract

Anticevic A, Cole MW, Repovs G, Savic A, Driesen NR, Yang G, Cho YT, Murray JD, Glahn DC, Wang XJ, Krystal JH. Connectivity, pharmacology, and computation:toward a mechanistic understanding of neural system dysfunction in schizophrenia. Front Psychiatry. 2013;4():169. Abstract

Murray JD, Anticevic A, Gancsos M, Ichinose M, Corlett PR, Krystal JH, Wang XJ. Linking microcircuit dysfunction to cognitive impairment:effects of disinhibition associated with schizophrenia in a cortical working memory model. Cereb Cortex. 2014 Apr;24(4):859-72. Abstract

Wang M, Yang Y, Wang CJ, Gamo NJ, Jin LE, Mazer JA, Morrison JH, Wang XJ, Arnsten AF. NMDA receptors subserve persistent neuronal firing during working memory in dorsolateral prefrontal cortex. Neuron. 2013 Feb 20;77(4):736-49. Abstract

Andreasen NC. The role of the thalamus in schizophrenia. Can J Psychiatry. 1997 Feb;42(1):27-33. Abstract

Woodward ND, Karbasforoushan H, Heckers S. Thalamocortical dysconnectivity in schizophrenia. Am J Psychiatry. 2012 Oct;169(10):1092-9. Abstract

Klingner CM, Langbein K, Dietzek M, Smesny S, Witte OW, Sauer H, Nenadic I. Thalamocortical connectivity during resting state in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2014 Mar;264(2):111-9. Abstract

Anticevic A, Cole MW, Repovs G, Murray JD, Brumbaugh MS, Winkler AM, Savic A, Krystal JH, Pearlson GD, Glahn DC. Characterizing Thalamo-Cortical Disturbances in Schizophrenia and Bipolar Illness. Cereb Cortex. 2013 Jul 3. Abstract

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