Learning from Drug Candidates—New Kid Targets Same Block

7 November 2008. Like any new kid on the block, the latest schizophrenia drug candidate has raised some eyebrows. Clinical trial results suggest that Eli Lilly’s metabotropic glutamate receptor activator, LY404039, treats positive and negative symptoms of schizophrenia with efficacy comparable to their current antipsychotic drug olanzapine (see SRF related meeting news and SRF related news story). The finding is both welcome and surprising. Welcome, because clinicians are currently limited to antipsychotic drugs that aim for just one molecular target, the dopamine D2 receptor. And surprising because it is not clear how a metabotropic glutamate agonist could have the same antipsychotic effects as dopamine antagonists.

The answer, at least for the orbitofrontal cortex, appears to be that though the drugs have different molecular targets, the end result is the same—they both restore activity of the same neurons. “This was very interesting because there is a lot of data, which is not discussed that much, implicating orbitofrontal cortex function in psychosis, cognitive dysfunction, and negative symptoms of schizophrenia,” said the study’s principal author, Bita Moghaddam, University of Pittsburgh, Pennsylvania. Disruptions to those three domains are characteristic of the disease.

Moghaddam and first author Houman Homayoun came to their conclusions by studying rodent models of schizophrenia. In one, NMDA (N-methyl-D-aspartate)-type glutamate neurotransmitter receptors are chemically blocked. This model has some validity since off-label, recreational use of such NMDA antagonists has been linked to schizophrenia-like episodes in humans, not to mention the fact that the original work that justified the Lilly trial was conducted by Moghaddam in the rat NMDA model. NMDA blockade disrupts neurotransmission in the prefrontal cortex (PFC), which encompasses the OFC, and many researchers believe that abnormalities in the PFC, specifically the dorsolateral PFC, are the key to better understanding and better treating the disease. In a second model the researchers treated rats with amphetamine, which activates dopaminergic circuits and has also been studied as a pharmacologic model for schizophrenia because it can cause psychosis (see SRF related news story).

By measuring the activity of individual neurons in vivo, the researchers found that the NMDA blockade activated regular-firing (RF) pyramidal neurons in the OFC, while inhibiting fast-firing (FF) interneurons. The researchers had previously reported that amphetamine has the same activation effect on RF neurons in the OFC, but not in the medial PFC (see Homayoun and Moghaddam, 2007). “What we saw was that in contrast to other cortical areas, two very different psychotomimetic drugs, NMDA antagonists and amphetamine, have very similar effects on the orbitofrontal cortex,” said Moghaddam. Amphetamine did not activate RF neurons in the medial PFC, which is the rodent equivalent of the human dorsolateral PFC. “That is key, that in another area that has been implicated in schizophrenia, and may be responsible for cognitive deficits, we are not seeing this shared effect, which seems to be selective to OFC,” she said.

If disruption of OFC neurotransmission is to blame for schizophrenia, as these models suggest, then one might expect antipsychotic drugs should restore normal OFC function. In fact, this is what the researchers found. When they pretreated rats with the approved antipsychotics haloperidol and clozapine, it reversed the effect of the NMDA receptor blocker, MK-801, and also reversed the effect of amphetamine. Interestingly, metabotropic NMDA receptor activators, of which Lilly’s LY404039 is one, had exactly the same effect. Homayoun and Moghaddam found that LY354740, an agonist for the mGlu2/3 type receptor, and the mGlu5 activator CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide), restored normal firing in RF neurons. These candidate schizophrenia drugs also reversed behavioral stereotypy, or repetitive movements, in the NMDA antagonist model. “For animal models of schizophrenia, stereotypy is a good measure because it reflects disruption to cortex-limbic interactions,” said Moghaddam.

While the dorsolateral PFC has been a major focus for schizophrenia researchers, the authors note that there are studies linking the disease to the OFC via studies of dopamine receptors (Meador-Woodruff et al., 1997) and DISC1 protein (Sawamura et al., 2005). DISC1, or disrupted in schizophrenia 1, is a major schizophrenia susceptibility gene candidate (see SRF related news story). Of course there are many potential gene candidates for the disease and one interesting facet of this work is that it ties in several types of neurons—dopaminergic, glutamatergic, and GABAergic—that have been implicated in various ways in schizophrenia. Looking at the disease as more of a neural network problem may help explain how a different group of genes can end up causing the same disease if they end up disrupting the same group of cells or the same network of cells, suggested Moghaddam. “I’m really optimistic, in that by starting to look at schizophrenia as more of a network disease, people may start thinking more creatively and be far more open to looking at different treatment options and novel targets,” she said.—Tom Fagan.

Reference:
Homayoun H, Moghaddam B. Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs. PNAS 2008 November 3 online.

The article by Homayoun and Moghaddam is another in an excellent series of articles investigating effects of metabotropic agents on brain function relevant to schizophrenia. As opposed to previous studies by this group that targeted rodent medial prefrontal cortex, which is used as a model of dorsolateral prefrontal cortex in humans, this study targets orbitofrontal cortex. The main finding of this study, like prior studies by this group, is that effects of the NMDA antagonist MK-801 can be reversed by the LY354740, a selective metabotropic group 2/3 agonist. LY354740 has previously been shown to reverse ketamine effects in humans (Krystal et al., 2005) and to be effective in treatment of generalized anxiety disorder in humans (Dunayevich et al., 2008). It is pharmacologically related to LY2130023 (Rorick-Kehn et al., 2007), a compound that has shown efficacy in treatment of schizophrenia (Patil et al., 2007).

In addition, the study builds upon prior studies of mGluR5 agonists (e.g., Darrah et al., 2008) to show that CDPPB, a novel modulator of mGluR5 receptors, also reverses acute effects of MK-801. mGluR5 receptors interact closely with NMDA receptors. It has been known for a long time that mGluR5 antagonists induce symptoms similar to those of NMDA antagonists, suggesting a potential role for agents that can stimulate mGluR5 activity. However, mGluR5 receptors are prone to downregulation following application of agonists, so the evaluation of mGluR5 receptors as a therapeutic target in schizophrenia has had to await development of high-affinity, CNS penetrant mGluR5 modulators that do not cause desensitization. The similar effects of an mGluR2/3 agonist and an mGluR5 modulator suggest that multiple approaches may be taken to normalize NMDA function in schizophrenia, including modulation of both presynaptic glutamate and postsynaptic NMDA function. mGluR5 receptors are active also in visual cortex (Sarihi et al., 2008), and so would potentially reverse effects of NMDA antagonists on sensory, as well as frontal deficits associated with schizophrenia.

In our own research studies, we have found that structural white matter alterations in orbitofrontal cortex correlate with ability to identify emotion (Leitman et al., 2007), attesting to the importance of this brain region to cognitive dysfunction in schizophrenia. Structural change in this region also correlates with aggression (Hoptman et al., 2005), which is an important issue determining clinical outcome in individuals with schizophrenia. Our findings thus support the concept that glutamatergic neurotransmission within orbitofrontal cortex may play as important a role in schizophrenia as dysfunction within dorsolateral prefrontal cortex, and deserves to be studied with equal fervor.

Despite the tremendous value of the study, every silver lining must have its cloud. In this case, the caveat relates to the finding that effects of MK-801 in this model were also reversed by haloperidol and clozapine. On the one hand, it is good news, as it suggests that metabotropic compounds may be as effective as antipsychotics in treating the well-known dopaminergic dysregulation associated with schizophrenia. In the one published clinical trial of LY2130023 (Patil et al., 2007), the compound proved almost as effective as olanzapine despite use of what may not have been an optimized dose.

On the other hand, however, it suggests that the orbitofrontal model, like the prior dorsolateral model, does not yet capture the aspects of schizophrenia that respond poorly to antipsychotics, such as primary negative symptoms and cognitive dysfunction. It is important to develop compounds that are as good as antipsychotics in treating positive symptoms, but without the well-known side metabolic and motor side effects. However, it is even more important to develop treatments that target aspects of schizophrenia that remain unresponsive to current therapeutic approaches. To date, no clinical data are available regarding effects of either mGlu2/3 agonists or mGlu5 modulators on neurocognition in humans. The ultimate challenge may be to show that metabotropic modulators can reverse effects of NMDA antagonists in models where antipsychotics such as haloperidol or clozapine prove ineffective. Another critical issue is whether these compounds will be effective during longer-term treatment (Imre et al., 2006). To do so, longer-term treatment studies are required. Nevertheless, these data provide further hope to the development of non-dopaminergic treatment approaches in schizophrenia.

References:

Darrah JM, Stefani MR, Moghaddam B. Interaction of N-methyl-D-aspartate and group 5 metabotropic glutamate receptors on behavioral flexibility using a novel operant set-shift paradigm. Behav Pharmacol. 2008 May 1;19(3):225-34. Abstract

Dunayevich E, Erickson J, Levine L, Landbloom R, Schoepp DD, Tollefson GD. Efficacy and tolerability of an mGlu2/3 agonist in the treatment of generalized anxiety disorder. Neuropsychopharmacology. 2008 Jun 1;33(7):1603-10. Abstract

Hoptman MJ, Volavka J, Weiss EM, Czobor P, Szeszko PR, Gerig G, Chakos M, Blocher J, Citrome LL, Lindenmayer JP, Sheitman B, Lieberman JA, Bilder RM. Quantitative MRI measures of orbitofrontal cortex in patients with chronic schizophrenia or schizoaffective disorder. Psychiatry Res. 2005 Nov 30;140(2):133-45. Abstract

Imre G, Fokkema DS, Ter Horst GJ. Subchronic administration of LY354740 does not modify ketamine-evoked behavior and neuronal activity in rats. Eur J Pharmacol. 2006 Aug 21;544(1-3):77-81. Abstract

Krystal JH, Abi-Saab W, Perry E, D'Souza DC, Liu N, Gueorguieva R, McDougall L, Hunsberger T, Belger A, Levine L, Breier A. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology (Berl). 2005 Apr 1;179(1):303-9. Abstract

Leitman DI, Hoptman MJ, Foxe JJ, Saccente E, Wylie GR, Nierenberg J, Jalbrzikowski M, Lim KO, Javitt DC. The neural substrates of impaired prosodic detection in schizophrenia and its sensorial antecedents. Am J Psychiatry. 2007 Mar 1;164(3):474-82. Abstract

Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med. 2007 Sep 1;13(9):1102-7. Abstract

Rorick-Kehn LM, Johnson BG, Burkey JL, Wright RA, Calligaro DO, Marek GJ, Nisenbaum ES, Catlow JT, Kingston AE, Giera DD, Herin MF, Monn JA, McKinzie DL, Schoepp DD. Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: in vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039). J Pharmacol Exp Ther. 2007 Apr 1;321(1):308-17. Abstract

Sarihi A, Jiang B, Komaki A, Sohya K, Yanagawa Y, Tsumoto T. Metabotropic glutamate receptor type 5-dependent long-term potentiation of excitatory synapses on fast-spiking GABAergic neurons in mouse visual cortex. J Neurosci. 2008 Jan 30;28(5):1224-35. Abstract

View all comments by Dan JavittComment by:  Henry Holcomb
Submitted 15 November 2008
Posted 15 November 2008

Homayoun and Moghaddam (PNAS) present important new data concerning the glutamatergic system and psychosis. They suggest the orbital frontal cortex (OFC) is particularly important in the pathophysiology of schizophrenia. They show that treatment with an NMDA receptor (NMDAR) antagonist induces OFC pyramidal neuron hyperactivity (secondary to GABA interneuron hypoactivity). This was reversed with haloperidol, clozapine, and a selective mGlu2/3 agonist, LY354740. This brief essay emphasizes how their findings support hypotheses of a common pathway in the biology of psychotic disorders. This group’s work (Adams et al., 2001; Moghaddam and Adams, 1998) contributes to an extensive body of research on the biology of psychosis. Human research shows that extensive frontal cortical systems and diverse molecular interactions may converge to form a common pathway to produce psychosis.

In their formulations of schizophrenia, Olney (Olney and Farber, 1995), Farber (Farber et al., 2002), and Tamminga (Tamminga et al., 1987) suggested a prominent role for disturbed glutamatergic neurotransmission. Human neurometabolic imaging studies using the NMDAR antagonist ketamine subsequently demonstrated marked brain metabolic hyperactivity. Using blood flow and glucose utilization as surrogate markers of neural activity investigators characterized the brain response to intravenous ketamine administration (Breier et al., 1997; Holcomb et al., 2005; Lahti et al., 1995; Vollenweider et al., 1997). Frontal and anterior cingulate (rostral component) regions of healthy volunteers and schizophrenic participants became hypermetabolic. But it is important to note that hypermetabolic response patterns are also generated in other human, psychotogenic drug models of psychosis. These include high dose amphetamine (Vollenweider et al., 1998), psilocybin (Gouzoulis-Mayfrank et al., 1999; Vollenweider et al., 1997), and cannabis (Mathew et al., 1989; O'Leary et al., 2007).

There is now compelling evidence to directly link cortical metabolic patterns to cortical glutamate/glutamine dynamics (Rothman et al., 1999). Rowland and colleagues’ magnetic resonance spectroscopy (MRS) study of ketamine given to healthy volunteers demonstrated a significant elevation in rostral anterior cingulate glutamine, a putative marker of increased glutamate release (Rowland et al., 2005). It seems reasonable to interpret Theberge and colleagues’ MRS study of never treated schizophrenia (Theberge et al., 2002) as a chemical confirmation of Soyka’s neurometabolic study, also of unmedicated schizophrenic patients (Soyka et al., 2005). Theberge found elevated glutamine in the anterior cingulate. Soyka found elevated glucose utilization in the frontal cortex. These studies, taken together, implicate increased glutamate release as a common mechanism in the pathology of early schizophrenia. Psychosis may arise from NMDA receptor antagonism (ketamine and PCP), stimulation of the 5-HT 2A-mGluR2 complex (psilocybin), or direct stimulation of the CB1 receptor on GABA interneurons (Katona and Freund, 2008). In each instance the consequence is an acute and robust glutamate release caused by disinhibition of pyramidal neurons.

Though Homayoun and Moghaddam have provided an elegant description of this phenomenon in the OFC, it is likely to be equally important in the medial and dorsolateral prefrontal cortex, as well as the anterior cingulate cortex. But the methodology and theory of this paper should help clinical investigators. The thoughtful study of metabotropic glutamatergic receptors and their clinical application (Patil et al., 2007) will go far to illuminate the subtle pathophysiology of psychosis.

References:

1. Adams BW, Moghaddam B: Effect of clozapine, haloperidol, or M100907 on phencyclidine-activated glutamate efflux in the prefrontal cortex. Biol. Psychiatry 2001; 50:750-757. Abstract

2. 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; 154:805-811. Abstract

3. Farber NB, Kim SH, Dikranian K, Jiang XP, Heinkel C: Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity. Mol. Psychiatry 2002; 7:32-43. Abstract

4. Gonzalez-Maeso J, Ang RL, Yuen T, Chan P, Weisstaub NV, Lopez-Gimenez JF, Zhou M, Okawa Y, Callado LF, Milligan G, Gingrich JA, Filizola M, Meana JJ, Sealfon SC: Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature 2008; 452:93-97. Abstract

5. Gouzoulis-Mayfrank E, Schreckenberger M, Sabri O, Arning C, Thelen B, Spitzer M, Kovar KA, Hermle L, Bull U, Sass H: Neurometabolic effects of psilocybin, 3,4-methylenedioxyethylamphetamine (MDE) and d-methamphetamine in healthy volunteers. A double-blind, placebo-controlled PET study with [18F]FDG. Neuropsychopharmacology 1999; 20:565-581. Abstract

6. Holcomb HH, Lahti AC, Medoff DR, Cullen T, Tamminga CA: Effects of noncompetitive NMDA receptor blockade on anterior cingulate cerebral blood flow in volunteers with schizophrenia. Neuropsychopharmacology 2005; 30:2275-2282. Abstract

7. Katona I, Freund TF: Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat. Med. 2008; 14:923-930. Abstract

8. Lahti AC, Holcomb HH, Medoff DR, Tamminga CA: Ketamine activates psychosis and alters limbic blood flow in schizophrenia. Neuroreport 1995; 6:869-872. Abstract

9. Mathew RJ, Wilson WH, Tant SR: Acute changes in cerebral blood flow associated with marijuana smoking. Acta Psychiatr. Scand. 1989; 79:118-128. Abstract

10. Moghaddam B, Adams BW: Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 1998; 281:1349-1352. Abstract

11. O'Leary DS, Block RI, Koeppel JA, Schultz SK, Magnotta VA, Ponto LB, Watkins GL, Hichwa RD: Effects of smoking marijuana on focal attention and brain blood flow. Hum. Psychopharmacol. 2007; 22:135-148. Abstract

12. Olney JW, Farber NB: NMDA antagonists as neurotherapeutic drugs, psychotogens, neurotoxins, and research tools for studying schizophrenia. Neuropsychopharmacology 1995; 13:335-345. Abstract

13. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD: Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat. Med. 2007; 13:1102-1107. Abstract

14. Rothman DL, Sibson NR, Hyder F, Shen J, Behar KL, Shulman RG: In vivo nuclear magnetic resonance spectroscopy studies of the relationship between the glutamate-glutamine neurotransmitter cycle and functional neuroenergetics. Philos. Trans. R. Soc. Lond B Biol. Sci. 1999; 354:1165-1177. Abstract

15. Rowland, L. M., Bustillo, J. R., Mullins, P. G., Jung, R. E., Lenroot, R., Landgraf, E., Barrow, R, Yeo, R, Lauriello, J, and Brooks, W. M. Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T Proton MRS study. Am. J. Psychiatry 162(2), 394-396. 2005. Abstract

16. Soyka M, Koch W, Moller HJ, Ruther T, Tatsch K: Hypermetabolic pattern in frontal cortex and other brain regions in unmedicated schizophrenia patients. Results from a FDG-PET study. Eur. Arch. Psychiatry Clin.Neurosci. 2005; 255:308-312. Abstract

17. Tamminga CA, Tanimoto K, Kuo S, Chase TN, Contreras PC, Rice KC, Jackson AE, O'Donohue TL: PCP-induced alterations in cerebral glucose utilization in rat brain: blockade by metaphit, a PCP-receptor-acylating agent. Synapse 1987; 1:497-504. Abstract

18. Theberge J, Bartha R, Drost DJ, Menon RS, Malla A, Takhar J, Neufeld RW, Rogers J, Pavlosky W, Schaefer B, Densmore M, Al Semaan Y, Williamson PC: Glutamate and glutamine measured with 4.0 T proton MRS in never-treated patients with schizophrenia and healthy volunteers. Am. J. Psychiatry 2002; 159:1944-1946. Abstract

19. 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; 7:9-24. Abstract

20. Vollenweider FX, Leenders KL, Scharfetter C, Maguire P, Stadelmann O, Angst J: Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology 1997; 16:357-372. Abstract

21. Vollenweider FX, Maguire RP, Leenders KL, Mathys K, Angst J: Effects of high amphetamine dose on mood and cerebral glucose metabolism in normal volunteers using positron emission tomography (PET). Psychiatry Res. 1998; 83:149-162. Abstract

View all comments by Henry Holcomb

Chronic phencyclidine administration remains the single best model for human psychosis. The crucial paper by Jentsch and colleagues (Jentsch et al., 1997), identifies every element needed for a satisfactory representation of the schizophrenia syndrome.

Though acute NMDA receptor antagonists induce hypermetabolism, prolonged phencyclidine induces a hypometabolic state (Wu et al., 1991; Tamminga et al., 1995) accompanied by severe dopaminergic disturbances (Aalto et al., 2005; Narendran et al., 2005).

Moghaddam's comments emphasize that there are multiple routes to psychosis, and these may converge on cortical glutamatergic/dopaminergic interactions (Narendran et al., 2005). But the numerous studies by her own group and those of Farber, Krystal, Vollenweider, Newcomer, Rowland, Tamminga, and Lahti suggest that there is much to be learned from additional work on the NMDA receptor antagonist preparation.

References:

Jentsch JD, Redmond DE Jr, Elsworth JD, Taylor JR, Youngren KD, Roth RH. Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. Science. 1997 Aug 15;277(5328):953-5. Abstract

Wu JC, Buchsbaum MS, Bunney WE. Positron emission tomography study of phencyclidine users as a possible drug model of schizophrenia. Yakubutsu Seishin Kodo. 1991 Feb;11(1):47-8. No abstract available. Abstract

Aalto S, Ihalainen J, Hirvonen J, Kajander J, Scheinin H, Tanila H, Nagren K, Vilkman H, Gustafsson LL, Syvalahti E, Hietala J. Cortical glutamate-dopamine interaction and ketamine-induced psychotic symptoms in man. Psychopharmacology (Berl). 2005 Nov;182(3):375-83. Epub 2005 Oct 19. Abstract

Narendran R, Frankle WG, Keefe R, Gil R, Martinez D, Slifstein M, Kegeles LS, Talbot PS, Huang Y, Hwang DR, Khenissi L, Cooper TB, Laruelle M, Abi-Dargham A. Altered prefrontal dopaminergic function in chronic recreational ketamine users. Am J Psychiatry. 2005 Dec;162(12):2352-9. Abstract

Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997 Apr 15;17(8):2921-7. Abstract

Farber NB, Kim SH, Dikranian K, Jiang XP, Heinkel C. Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity. Mol Psychiatry. 2002;7(1):32-43. Abstract

Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, Heninger GR, Bowers MB Jr, 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

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

Newcomer JW, Farber NB, Jevtovic-Todorovic V, Selke G, Melson AK, Hershey T, Craft S, Olney JW. Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology. 1999 Feb;20(2):106-18. Abstract

Rowland LM, Bustillo JR, Mullins PG, Jung RE, Lenroot R, Landgraf E, Barrow R, Yeo R, Lauriello J, Brooks WM. Effects of ketamine on anterior cingulate glutamate metabolism in healthy humans: a 4-T proton MRS study. Am J Psychiatry. 2005 Feb;162(2):394-6. Abstract

Tamminga CA, Holcomb HH, Gao XM, Lahti AC. Glutamate pharmacology and the treatment of schizophrenia: current status and future directions. Int Clin Psychopharmacol. 1995 Sep;10 Suppl 3:29-37. Abstract

Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA. Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology. 2001 Oct;25(4):455-67. Abstract

View all comments by Henry Holcomb

Related News: Modeling Psychosis in Prefrontal Cortex—The Effects of Amphetamine

Comment by:  Elizabeth Ryan
Submitted 7 October 2006
Posted 7 October 2006
  I recommend the Primary Papers

Excellent overview. My daughter has been addicted to meth for over twenty years and I AM seeing her inability to make constructive, long-term decisions, even when "clean." Our oldest son has schizophrenia, and although he is highly functioning, shows some of the impairment(s) my daughter exhibits.

View all comments by Elizabeth Ryan

Related News: Modeling Psychosis in Prefrontal Cortex—The Effects of Amphetamine

Comment by:  J David Jentsch
Submitted 21 November 2006
Posted 22 November 2006
  I recommend the Primary Papers

Moghaddam is correct in arguing that long-term intake of, or exposure to, amphetamine-like drugs produces a spectrum of changes in cortical and subcortical function that underlie cognitive and affective abnormalities that relate to the abuse potential of the drugs, as well as the associated drug-induced psychotic symptoms. This may be particularly true for methamphetamine (Yui et al., 1999). Indeed, Jane Taylor and I proposed 7 years ago now (Jentsch and Taylor, 1999) that dysregulation of frontal cortical function is a common feature of long-term exposure to drugs of abuse; today, this is a phenomenon that is generally accepted as contributing directly to the addictive process (London et al., 2000; Everitt et al., 2001; Robinson and Berridge, 2003; Goldstein and Volkow, 2002; Lubman et al., 2004). In that sense, the concept that amphetamine alters frontal lobe function in important ways relevant to both addictive and psychotic disorders is hardly new.

A separate question touched upon in the article and subsequent discussion is whether either amphetamine or phencyclidine represents a more informative or valid model for schizophrenia and/or its symptoms than the other.

For nearly 60 years, investigators have used amphetamine-like and phencyclidine-like drugs to simulate psychopathological states in human beings and animals that correspond (to varying degrees) with sequelae of schizophrenia. One clear issue that has emerged from the 6 decades of research is that these two drugs produce some similar and some different effects on behavior, which is not surprising, owing to their distinctive pharmacologic and neurochemical mechanisms of action. What is unfortunate is that the apparent differences have led to a history of conflict over which represents the better model for psychotic disorders. In opposition to the overly dogmatic arguments of those in favor of one approach or the other, I argue that we should focus on the commonalities of the action of these two classes of agents to find the mechanisms that will ultimately have the broadest implications for understanding schizophrenia.

What is clear is that, under the right conditions (dose, route of administration, frequency and duration of exposure, etc.), people who are passively exposed to these drugs or who voluntarily consume them can show psychopathological states that include behavioral dimensions of psychotic disorders; this is markedly different from a drug like nicotine which virtually never does. Although these agents very specifically produce psychopathology of interest to schizophrenia researchers, the “right conditions” required for each to achieve temporary or persistent psychotomimetic effects are not known. For example, it is simply not clear what determines which methamphetamine abusers will develop psychotic symptoms and which will not (is it ethnicity, age of onset, total lifetime dose, underlying genetic risk?).

If we knew what the right conditions were for both drugs and could mimic those in animals, I believe that we would find a common set of neuroadaptations in the prefrontal cortex and its striato-pallido-thalamic targets that represent the final common pathway by which these two otherwise distinct agents dysregulate the normal mental and emotional function of animals and people who are exposed to them. I further propose that, if we knew the right conditions under which cannabis induced psychotic symptoms, it would point to the same pathway. At this nexus, we will additionally discover mechanisms that help to explain the comorbidity between substance abuse and psychotic disorders, as the common features for all of these agents is their abuse liability and psychotomimetic properties.

Without the information about the right conditions, the conflict over the validity of amphetamine versus phencyclidine models is unresolvable. Clearly, there are many studies in which one or the other drug was given to animals with little behavioral, physiological, or anatomical feature of schizophrenia being induced. But this is not because there is no general validity for either model; it is because we haven’t learned quite yet what the conditions are under which these drugs affect people in a manner relevant to the field and should be expected to affect animals.

At the current time, concluding that one or the other model is better (whatever that means, in scientific terms) or is more accurate in its ability to induce a model for the disorder is premature.

References:

Everitt BJ, Dickinson A, Robbins TW. The neuropsychological basis of addictive behaviour. Brain Res Brain Res Rev. 2001 Oct;36(2-3):129-38. Review. Abstract

Goldstein RZ, Volkow ND. Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry. 2002 Oct;159(10):1642-52. Review. Abstract

Jentsch JD, Taylor JR. Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology (Berl). 1999 Oct;146(4):373-90. Review. Abstract

London ED, Ernst M, Grant S, Bonson K, Weinstein A. Orbitofrontal cortex and human drug abuse: functional imaging. Cereb Cortex. 2000 Mar 1;10(3):334-42. Abstract

Lubman DI, Yucel M, Pantelis C. Addiction, a condition of compulsive behaviour? Neuroimaging and neuropsychological evidence of inhibitory dysregulation. Addiction. 2004 Dec;99(12):1491-502. Review. Abstract

Robinson TE, Berridge KC. Addiction. Annu Rev Psychol. 2003;54:25-53. Epub 2002 Jun 10. Review. Abstract

Yui K, Goto K, Ikemoto S, Ishiguro T, Angrist B, Duncan GE, Sheitman BB, Lieberman JA, Bracha SH, Ali SF. Neurobiological basis of relapse prediction in stimulant-induced psychosis and schizophrenia: the role of sensitization. Mol Psychiatry. 1999 Nov;4(6):512-23. Review. Abstract

View all comments by J David Jentsch

Related News: Modeling Psychosis in Prefrontal Cortex—The Effects of Amphetamine

Comment by:  J. Daniel Ragland
Submitted 13 December 2006
Posted 13 December 2006
  I recommend the Primary Papers

The acknowledgment that amphetamine psychosis (like schizophrenia) can have inverse effects (both hypo- and hyperfunction) on different regions of the prefrontal cortex (PFC) is an important one, and worth emphasizing. There is regional specificity of effects within the PFC, not just a global increase or decrease in function. In addition to the distinction between the orbital and medial PFC mentioned in the article, there is converging evidence from the working memory imaging literature that schizophrenia may have inverse effects on ventrolateral (VLPFC) and dorsolateral (DLPFC) prefrontal cortex, with increased VLPFC and decreased DLPFC activation in schizophrenia (Glahn et al., 2005). This has potentially important implications for understanding compensatory performance strategies, and for devising cognitive remediation interventions.

References:

Glahn, D.C., Ragland, J.D., Abramoff, A., Barrett, J., Laird, A.R., Bearden, C.E., Velligan, D.I.: Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia. Hum Brain Mapp. 2005 May;25(1):60-9. Abstract

View all comments by J. Daniel Ragland

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

Print this page