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

  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

  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

  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