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ICOSR 2011—Some Hope for Alleviating Negative Symptoms

The International Congress on Schizophrenia Research, Version 13.0, has come and gone. The 2011 Congress in Colorado Springs, Colorado, attracted nearly 1,200 attendees to the Broadmoor Hotel from 2-6 April 2011, not to mention the satellite meetings on cognition and the schizophrenia prodrome. With the gracious assistance of conference directors Carol Tamminga and Chuck Schulz, as well as meeting staff Dorothy Denton and Cristan Tamminga, SRF will once again be bringing you meeting reports from Young Investigator awardees, in addition to SRF writers.


15 April 2011. The standing ICOSR session on pharmacotherapeutic advances has not offered much to write about in recent times, with the exception of the 2007 report of a successful trial of Eli Lilly and Company's metabotropic glutamate receptor agonist (see SRF related news story). Even that story has grown complicated with the increasing placebo response that plagues psychiatric clinical trials (see SRF 2009 related news story).

Some hopeful signs appeared at the new drug session of this year's meeting on 4 April 2011, however. "A couple of compounds that were developed for cognitive impairment in schizophrenia have shown effects on negative symptoms," session co-chair Steve Marder of UCLA told SRF, referring to two α7 nicotinic cholinergic drugs and the glycine transporter inhibitor RG1678. Here, we briefly summarize these and other possibilities in the pipeline.

The atypicals
Peter Weiden of the University of Illinois, Chicago, kicked off the "New Drug Session: Advances in Medication Development and Assessment" with an update on the atypical antipsychotic iloperidone, which has been approved for use in the United States since the last ICOSR meeting was held. It has a hypothesized dopamine D2/5HT mechanism of action, and many studies show antipsychotic efficacy with only relatively modest weight gain (perhaps in the same range as risperidone) and favorable metabolic markers. There is also little evidence that it causes extrapyramidal symptoms, Weiden reported.

Anthony Loebel of Sunovion, Inc., Fort Lee, New Jersey, then gave an update on lurasidone, highlighting its approval in the U.S. last fall, and the fact that it first became available in February of this year. It is also a D2/5HT antagonist, but Loebel cited evidence that it has some unique qualities in terms of affinity for several of the serotonin receptors, especially 5HT7. He described the side effect profile as being good on both weight gain and metabolic markers, but there is evidence for some extrapyramidal symptoms and akathisia.

He was followed by Ronald Landbloom of Merck and Co., Rahway, New Jersey, who reported on asenapine. Landbloom highlighted a receptor profile that also shows high affinity for DRD2 and some 5HT subtypes, but low affinity for muscarinic cholinergic receptors. As have others, Landbloom and colleagues are seeing high placebo response rates in their trials. He described asenapine’s effect on weight gain and metabolic markers as limited, though there is evidence of greater rates of akathisia relative to placebo in the trials reported.

Anyone excited by glutamate?
There is always an interest in updates on development of mGluR2/3 agonists, and Bruce Kinon from Lilly's labs in Indianapolis, Indiana, reviewed some of the data Lilly has generated over the past several years in animal models (see, e.g., Rorick-Kehn et al., 2007; Fell et al., 2009). In particular, Kinon said, the preclinical data suggest the possibility of synergism between mGluR2/3 agonists and D2 blockers, pointing to the obvious question of whether the mGluR2/3 drugs could enhance responses to current antipsychotic drugs (see SRF related meeting story).

Moving to the ongoing patient trials, Kinon said that Lilly does not have the final story in hand on the efficacy of mGluR2/3 agonists as monotherapy. Acute efficacy testing is underway on the mGluR2/3 agonist LY2140023 monohydrate, an oral pro-drug of LY404039. Kinon mentioned a recent open-label safety study on patients with pronounced negative symptoms. Efficacy data from this study suggest some significant improvement, indicated by increases in PANSS scores in the LY2140023-treated group. He also tantalized the audience with hints that Lilly's pharmacogenetic data suggest that variation in the genes for the 5HT2A receptor and the protein neuregulin can help predict who will respond well to mGluR2/3 agonists.

The other major direction of research that follows from the glutamate hypothesis of schizophrenia (see SRF hypothesis papers by Bita Moghaddam and Daniel Javitt) attempts to boost activation of the NMDA receptor via a glycine-centered approach (see SRF related news story). The NMDA receptor requires that both the amino acid glycine and the neurotransmitter glutamate (or aspartate) bind to it, at separate sites, in order for ions to flow through.

Daniel Umbricht of F. Hoffmann-La Roche, Ltd., Basel, Switzerland, reported on continuing work that aims to provide more glycine to the NMDA receptor by interfering with the glycine transporter molecule as it goes around mopping up spare glycine. The inhibitor RG1678 has shown in some trials that it might be effective as an add-on therapy, and Umbricht presented data indicating that this drug improves negative symptoms better than placebo. Because the effect seemed to increase towards the end of the eight-week trial, they are continuing the study to determine if the improvement persists. He also mentioned that the data indicate that the drug’s efficacy depends on low doses.

Agonizing nicotinic receptors
The α7 nicotinic cholinergic receptor is a popular target for boosting cognition in schizophrenia, and also in Alzheimer’s and other diseases (see the series of meeting reports produced by the Alzheimer Research Forum). The early news on manipulating the α7 receptor in schizophrenia was not compelling (see SRF related news story); however, Robert Freedman, University of Colorado, Denver, presented additional analyses of data from an earlier study on the partial nicotinic agonist DMXB-A, which point to pro-cognitive effects in nonsmokers. Interestingly, Freedman reported that the drug appeared to improve negative symptoms as well.

The effects on negative symptoms were echoed in a presentation by David Hosford of Targacept, Inc., Winston-Salem, North Carolina. Targacept's drug, TC-5619, is a full, selective agonist at the α7 receptor, Hosford said. A newly completed Phase 2 trial found statistically significant improvements over placebo in both the cognitive and negative symptom domains. In contrast to the data that Freedman reported, smokers seemed to drive the improvement for this drug, in this trial.

And now for some things completely different…
Jeff Anderson, from Cypress Bioscience of San Diego, California, was one of three speakers who described different tacks to schizophrenia treatment. Originally developed by the Israeli company BioLineRx, the Cypress compound Cyp-1020 features the typical antipsychotic perphenazine with the neurotransmitter γ-aminobutyric acid (GABA) attached to it. The logic is that enhancing GABA transmission might be effective against cognitive symptoms of schizophrenia (see SRF Interview with David Lewis), although there has been no clinical success with this approach yet (see SRF related news story). Anderson said that this hypothesis was supported by animal studies that found pro-cognitive effects of Cyp-1020, but not perphenazine alone.

In their six-week Phase 2 study of Cyp-1020, Cypress found significant improvement in cognitive tests over both risperidone and placebo, Anderson said. He noted that the occurrence of extrapyramidal side effects was comparable between the two drugs. This study was limited to acutely ill patients, and the researchers are now studying longer-term effects.

The next talk featured the drug ITI-007, from Intra-Cellular Therapies. Originally developed by Bristol-Myers Squibb Company, it is an antagonist at both dopamine D2 receptors and 5HT2A receptors, though it has a much higher affinity for the serotonergic receptors. Because it also acts as an intracellular inhibitor of pathways downstream of the D2 receptor, the notion is that, if the doses are kept low enough, the drug would block the 5HT2A receptor, but also function as an antipsychotic. Since it barely blocks D2, it may avoid extrapyramidal symptoms.

Kimberly Vanover of Intra-Cellular Therapies, New York, said that with this drug they are going after sleep deficits, depression, and cognitive deficits linked to sleep, as well as psychosis. In studies to date, both in insomnia patients without schizophrenia and patients with schizophrenia, the drug is well tolerated and promotes sleep. The next step will be to assess its efficacy in schizophrenia.

Both of these compounds represent novel approaches but fit within the usual synaptic transmission framework. The last study of the session, presented by Dan Javitt, Nathan Kline Institute, Organgeburg, New York, was something completely different. He spoke about davunetide, the more friendly name of the peptide NAPVSIPQ (or NAP). This fragment of activity-dependent neuroprotective protein (ADNP) helps stabilize microtubules, restoring neuronal structure and function.

Although the evidence for neuronal lesions in schizophrenia remains vague, the drug is in development for disorders such as Alzheimer’s disease because of evidence that it improves cognitive function in animal models of neurodegenerative disease. Thus, the Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) program selected it for a clinical trial as adjunctive therapy in schizophrenia. Javitt reported that, in a very small sample, davunetide produced non-significant improvements on primary cognition measures that warrant more study. This assessment was reinforced, he said, by positive results from secondary outcome assessments.

Open, public discourse
"I like the breadth of the presenters and ideas," co-chair of the session, ICOSR co-director Chuck Schulz of the University of Minnesota told SRF. "Different modes of action of medicines, different levels, ranging from pilot data through Phase 3. And I like that people from different sectors come together." Indeed, said Schulz, this was one of the purposes of the New Drugs session when it was instituted many Congresses ago: to prevent the traditional Balkanization of researchers at conferences—sessions geared only toward academic or industry scientists, or even toward a single company.

Though he wasn't surprised by any of the compounds, Schulz said, "I thought the idea of the perphenazine-GABA conjugate was great. That was new stuff." His co-chair, Marder, was hopeful that the session both reflected and could spur a renewed interest in developing drugs for negative symptoms of schizophrenia.—Hakon Heimer.

Comments on News and Primary Papers
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

Comments on Related News


Related News: ICOSR 2007—Glutamate Regulator May Be Alternative to D2 Blockers

Comment by:  Patricia Estani
Submitted 21 May 2007
Posted 21 May 2007

In the field of the psychopharmacology of schizophrenia, a lot of research work has been done on dopaminergic systems. Thus, this research news is excellent news because it explores an alternative neurotransmission system in schizophrenia, the glutamatergic system. Since the work of Dr. Bita Moghaddam in 1998, published in Science, a lot of research studies have turned to the important role of glutamate in schizophrenia. More studies are needed to focus on the exact role of this neurotransmitter.

View all comments by Patricia Estani

Related News: ICOSR 2007—Glutamate Regulator May Be Alternative to D2 Blockers

Comment by:  Joseph Neale
Submitted 14 July 2007
Posted 14 July 2007

The pioneering research over the past decade on group II metabotropic glutamate receptor (mGluR) agonists from the Lilly Labs and Bita Moghaddam's research group has provided a strong foundation for the view that activation of these receptors reduces schizophrenia-like behaviors in the PCP and amphetamine models. These phase 2 clinical trials bring mGluR agonists one step closer to clinical use as therapy or co-therapy.

These same data provide the foundation for current and future research aimed at increasing the concentration of the peptide transmitter, N-acetylaspartylglutamate (NAAG) in the synaptic cleft by systemic administration of NAAG peptidase inhibitors. NAAG is the third most prevalent transmitter in the mammalian nervous system and a selective group II mGluR agonist with preference for mGluR3 (Neale et al., 2005). Our research group demonstrated that a NAAG peptidase inhibitor substantially reduces positive and negative behaviors induced in PCP models of schizophrenia (Olszewski et al., 2007; Olszewski et al., 2004). These NAAG peptidase inhibition studies parallel the preclinical studies from Lilly and Bita Moghaddam on mGluR agonists in animal models of schizophrenia. Since NAAG is an endogenous transmitter, it can be argued that elevating its levels following synaptic release by reducing the rate of its inactivation (analogous to SSRI and serotonin) is a more physiologic means of activating the mGluR, and thus this may be better tolerated with fewer side effects than the continuous receptor activation that is obtained via systemic administration of a receptor agonist.

These phase 2 clinical trials clearly brighten the prospects for both lines of new drug development for treatment of schizophrenia.

References:

Neale JH, Olszewski RT, Gehl LM, Wroblewska B, Bzdega T. The neurotransmitter N-acetylaspartylglutamate in models of pain, ALS, diabetic neuropathy, CNS injury and schizophrenia. Trends Pharmacol Sci. 2005 Sep;26(9):477-84. Review. Abstract

Olszewski RT, Wegorzewska MM, Monteiro AC, Krolikowski K, Zhou J, Kozikowski AP, Long K, Mastropaolo J, Deutsch S, Neale JH. PCP and MK-801 induced behaviors reduced by NAAG peptidase inhibition via metabotropic glutamate receptors. E-pub in advance of print, Biological Psychiatry, 2007.

Olszewski RT, Bukhari N, Zhou J, Kozikowski AP, Wroblewski JT, Shamimi-Noori S, Wroblewska B, Bzdega T, Vicini S, Barton FB, Neale JH. NAAG peptidase inhibition reduces locomotor activity and some stereotypes in the PCP model of schizophrenia via group II mGluR. J Neurochem. 2004 May;89(4):876-85. Abstract

View all comments by Joseph Neale

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: New Schizophrenia Drug Studies Offer Threads of Hope

Comment by:  John Michael Brummer
Submitted 6 September 2008
Posted 6 September 2008
  I recommend the Primary Papers

Related News: GABA Receptor Drug for Schizophrenia Is Put Through Its Paces

Comment by:  Robert McCarley
Submitted 7 November 2008
Posted 7 November 2008

This paper is further evidence of an important and laudable new trend in schizophrenia psychopharmacology: namely the development and test of compounds on the basis of their relationship to circuit abnormalities, evidence derived from postmortem, genetic, and animal model studies. The authors based their choice of MK-0777 for test in schizophrenia on evidence for decreased cortical GABA neurotransmission onto pyramidal neurons at receptors having the α2 subunit, and other evidence pointing to the GABA-pyramidal neuron interaction as important in cognition and in generation of γ band oscillations. In this add-on, double-blind placebo study, the Ns were underpowered and more subjects need to be studied to be certain about clinical effects. However, one test, the Preparing to Overcome Prepotency Test (POP), had significant improvements in response latency and showed concomitant improvement in increased frontal γ band activity induced during the task, although not meeting the criterion for statistical significance. POP requires subjects either to “go with the flow” (indicated by a green light) and respond in the same direction as an arrow, or when cued by a red light to “go upstream” and point in the opposite direction, a test previously used in the Cho et al. 2006 PNAS paper and found to be accompanied by increased induced γ band oscillations.

γ band activity has justifiably attracted considerable attention, since there is mounting evidence of its relevance to human cognition as well as to basic neuroscience studies of neuronal assembly communication. Its important basis in the GABA cortical neuronal interaction with pyramidal cells makes it especially fascinating in schizophrenia. However, an important caution light was recently flashed by Yuval-Greenberg et al. in an article in Neuron (2008) in which they presented strong evidence that apparent increases or decreases in the “induced γ band oscillations” (those not temporally linked to a response or stimulus) could be the result of the eye muscle activation associated with small saccadic eye movements, “a saccadic spike potential” that could be confused with γ band oscillations. The Yuval-Greenberg article appeared too late for the authors to discuss in the present paper, but its implications for future work using induced γ are important. For studies of induced γ, we all will have to begin using eye movement measures sensitive to mini-saccades. Those of us who measure γ phase-locked to measureable events, such as sensory stimuli or responses, appear to be off the hook since we condition on known events, unlike conditions where induced γ is measured.

References:

Cho RY, Konecky RO, Carter CS. Impairments in frontal cortical gamma synchrony and cognitive control in schizophrenia. Proc Natl Acad Sci U S A. 2006 Dec 26;103(52):19878-83. Abstract

Yuval-Greenberg S, Tomer O, Keren AS, Nelken I, Deouell LY. Transient induced gamma-band response in EEG as a manifestation of miniature saccades. Neuron. 2008 May 8;58(3):429-41. Abstract

View all comments by Robert McCarley

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

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 Seeman

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

Comment 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