Comments on News and Primary Papers
Primary Papers: Antipsychotic drugs reverse the disruption in prefrontal cortex function produced by NMDA receptor blockade with phencyclidine.Comment by: Dan Javitt, SRF Advisor
Submitted 13 September 2007
Posted 13 September 2007
PCP model forges ahead
What is the true cause of schizophrenia? Over the past 50 years, the amphetamine and PCP models have been fighting it out. Amphetamine got out to an early lead, mostly because it was discovered first, and PCP has been playing catch-up ever since. One way to keep score with these models is to track citations in general “high-profile” science journals such as PNAS for (dopamine or D2) vs. (glutamate or NMDA), and schizophrenia.
Since 1967, in MEDLINE, the amphetamine model has a commanding lead, 35 cites to 19. However, since 2004, the two models are exactly equal, with 12 cites each. With this article, glutamate forges out to a commanding lead.
The article by Kargieman and colleagues also points out the importance of delta rhythms as indices of thalamocortical activity. The finding that PCP disrupts delta rhythmicity resonates with the emerging literature on slow-wave sleep reductions in schizophrenia. The finding that clozapine reverses PCP-induced disruption of delta sleep is consistent with improvements in slow-wave sleep that have been reported with several atypical antipsychotics, including risperidone and olanzapine. The challenge is to isolate the mechanism of action of clozapine, and to design more specific and more effective agents.
In Science, amphetamine has a commanding 40 to 7 lead in MEDLINE, but PCP and amphetamine are tied at 1 and 1 since 2004. The game is on.
View all comments by Dan JavittComment by: J David Jentsch
Submitted 16 September 2007
Posted 17 September 2007
The article by Kargieman and colleagues further specifies the cellular mechanisms underlying the actions of clozapine in a model of pharmacologically induced cortical dysfunction. Separately, clozapine has been demonstrated to be capable of reducing or eliminating the complex behavioral and cognitive impairments elicited by acutely administered NMDA antagonists (Geyer et al., 2001; Idris et al., 2005; Lipina et al., 2005), and these cellular mechanisms shown by Kargieman et al. may represent the level of interaction between clozapine and phencyclidine-like drugs.
What is surprising from so many of these studies is the quality of the reversal of effects produced by clozapine, despite the fact that it (like most other antipsychotic drugs) has limited efficacy both at an individual and population level. Furthermore, there remain many reports in the literature demonstrating that while some cognitive and symptomatic domains in schizophrenia are improved by clozapine, others clearly are not (Goldberg and Weinberger, 1996; Bilder et al., 2002). Why, then, is clozapine so effective in the PCP model? One concern, of course, is that its effects are related to a specific type of pharmacological interaction; one certainly needs to see clozapine's effects in other models that do not involve the acute administration of an NMDA antagonist.
Notably, several groups have been studying the effects of long-term administration of phencyclidine, sometimes followed by washout of the NMDA antagonist, to develop an alternative type of model that may depend upon the neuroadaptations resulting from blockade of NMDA receptors, rather than on the acute pharmacological action itself (Jentsch et al., 1997; Balla et al., 2003; Amitai et al., 2007, and many others). Whilst the specific validity of any one of these approaches is debatable, what appears to be clear is that the ability of clozapine to reverse behavioral or neurochemical deficits is much more tenuous. Is this a weakness of these models, or does it mean they are actually more realistic in their predictions?
Based upon these facts, one is left with a number of questions. First, is a model that predicts that clozapine is completely effective at blocking psychopathology or pathophysiology valid? Second, is the action of clozapine in any one model based upon one kind of manipulation really that provocative? And finally (and perhaps most importantly), is developing models that explain how clozapine works really in our best interest, or is it time to move beyond models that predict marginal gains from existing drugs, in order to look to targets flowing from the new valid genetic mechanisms that appear to hold the keys to the next generation of treatments for schizophrenia?
Amitai N, Semenova S, Markou A. Cognitive-disruptive effects of the psychotomimetic phencyclidine and attenuation by atypical antipsychotic medications in rats. Psychopharmacology (Berl). 2007 Sep;193(4):521-37. Abstract
Balla A, Sershen H, Serra M, Koneru R, Javitt DC. Subchronic continuous phencyclidine administration potentiates amphetamine-induced frontal cortex dopamine release. Neuropsychopharmacology. 2003 Jan;28(1):34-44. Abstract
Bilder RM, Goldman RS, Volavka J, Czobor P, Hoptman M, Sheitman B, Lindenmayer JP, Citrome L, McEvoy J, Kunz M, Chakos M, Cooper TB, Horowitz TL, Lieberman JA. Neurocognitive effects of clozapine, olanzapine, risperidone, and haloperidol in patients with chronic schizophrenia or schizoaffective disorder. Am J Psychiatry. 2002 Jun;159(6):1018-28. Abstract
Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl). 2001 Jul;156(2-3):117-54. Abstract
Goldberg TE, Weinberger DR. Effects of neuroleptic medications on the cognition of patients with schizophrenia: a review of recent studies. J Clin Psychiatry. 1996;57 Suppl 9:62-5. Abstract
Idris NF, Repeto P, Neill JC, Large CH. Investigation of the effects of lamotrigine and clozapine in improving reversal-learning impairments induced by acute phencyclidine and D-amphetamine in the rat. Psychopharmacology (Berl). 2005 May;179(2):336-48. Abstract
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
Lipina T, Labrie V, Weiner I, Roder J. Modulators of the glycine site on NMDA receptors, D-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia. Psychopharmacology (Berl). 2005 Apr;179(1):54-67. Abstract
View all comments by J David JentschComment by: Jeremy Seamans
Submitted 28 September 2007
Posted 28 September 2007
The paper by Kargieman et al. provides an interesting perspective on the effects of PCP on activity in the prefrontal cortex. Dr. Javitt brings up an excellent point in his commentary that the study highlights the importance of PCP in this preparation as a model of slow-wave sleep disturbances in schizophrenia. In anesthetized animals, field potential recordings resemble the up and down states observed in slow-wave sleep. These states are driven by NMDA receptors and, accordingly, NMDA antagonists such as PCP and ketamine should reduce them as reported. The odd thing about NMDA antagonists is that they themselves can be used as anesthetics to produce a state where slow delta oscillations predominate. For instance, robust up and down states or slow oscillations at or below delta are observed when ketamine is used as an anesthetic. Therefore, NMDA antagonists can induce a state where delta activity is prominent, yet if the subject is already in that state, the effect of the drug is to reduce such activity.
So this also may be the case with PCP. There are numerous EEG studies showing that PCP significantly increases activity in the delta band of awake humans or animals (Stockard et al., 1976; Matsuzaki and Dowling, 1985; Mattia et al.,1988; Marquis et al., 1989; Yamamoto, 1997; Sebban et al., 2002), yet reduces power in this band of anesthetized animals. Moreover, schizophrenics appear to have a significant increase in frontal delta oscillations when awake (Wuebben and Winterer, 2001), yet exhibit slow-wave sleep disturbances and lower delta count when asleep (Ganguli et al., 1987). How is that?
It may be a matter of perspective. In the awake state the cortex is highly desynchronized and firing is quite irregular with power in a variety of high-frequency bands and neurons firing at every phase angle of the field potential. With anesthetics, higher frequencies become unsustainable. Using realistic network model simulations, Durstewitz and Gabriel (2007) showed that if you come from a regime which is quite irregular and then reduce NMDA, you get clear delta wave oscillations, but as you keep reducing NMDA, these delta oscillations will become progressively reduced as well. So in the awake state, reductions in NMDA currents should relatively decrease power in many bands yet enhance delta, but if the network is already in delta, as when the subject is anesthetized or asleep, NMDA reduction would decrease power in this band. Therefore, the results of Kargieman et al., when viewed in light of the literature obtained in awake subjects and schizophrenics, confirms a non-trivial and somewhat paradoxical prediction of the NMDA theory of schizophrenia and the PCP model.
Durstewitz D, Gabriel T. Dynamical basis of irregular spiking in NMDA-driven prefrontal cortex neurons.
Cereb Cortex. 2007 Apr;17(4):894-908. Epub 2006 Jun 1.
Ganguli R, Reynolds CF 3rd, Kupfer DJ. Electroencephalographic sleep in young, never-medicated schizophrenics. A comparison with delusional and nondelusional depressives and with healthy controls.
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Marquis KL, Paquette NC, Gussio RP, Moreton JE. Comparative electroencephalographic and behavioral effects of phencyclidine, (+)-SKF-10,047 and MK-801 in rats.
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Matsuzaki M, Dowling KC. Phencyclidine (PCP): effects of acute and chronic administration on EEG activities in the rhesus monkey.
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Mattia A, Marquis KL, Leccese AP, el-Fakahany EE, Moreton JE. Electroencephalographic, behavioral and receptor binding correlates of phencyclinoids in the rat.
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Sebban C, Tesolin-Decros B, Ciprian-Ollivier J, Perret L, Spedding M. Effects of phencyclidine (PCP) and MK 801 on the EEGq in the prefrontal cortex of conscious rats; antagonism by clozapine, and antagonists of AMPA-, alpha(1)- and 5-HT(2A)-receptors.
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Stockard JJ, Werner SS, Aalbers JA, Chiappa KH. Electroencephalographic findings in phencyclidine intoxication.
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Wuebben Y, Winterer G. Hypofrontality -- a risk-marker related to schizophrenia?
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Yamamoto J. Cortical and hippocampal EEG power spectra in animal models of schizophrenia produced with methamphetamine, cocaine, and phencyclidine.
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View all comments by Jeremy Seamans