Schizophrenia models

While the obvious value of in vivo animal models is clear, there also are instances—especially in cases of inflammatory arthritis, behavior, and tumor growth—where they have failed to be predictive of useful clinical activity in humans [51], For example, leukotriene (LTB4) antagonists showed activity in animal models of inflammatory arthritis yet failed to be useful in rheumatoid arthritis [52]. Similarly, dopamine D4 antagonists showed activity in animal behavior models previously predictive of dopamine D2 antagonists in schizophrenia. However, testing of dopamine D4 antagonists showed no efficacy in humans [53]. 

For many years it was believed that the brain mechanisms underlying the effects of psychedelic hallucinogens and dissociative anesthetics were separate and distinct. Indeed, there has been considerable debate about which represents the best drag model of schizophrenia. However, recent data show that the two classes of psychotomimetic drags share a common final pathway involving an increase in the release of the excitatory neurotransmitter glutamate. 

Abi-Saab WM, D Souza DC, Moghaddam B et al (1998) The NMDA antagonist model for schizophrenia promise and pitfalls. Pharmacopsychiatry (Suppl)31 104—109... 

Wound healing Schizophrenia (mouse knockout model) ... 

Trial validity is also grossly affected by the type of trial carried out. In schizophrenia there are several health-care decision models, retrospective mirror-image analyses (with or... 

Palmer CS, Revicld DA, Genduso LA, et al (1998). A cost-effectiveness clinical decision analysis model for schizophrenia. Am J Managed Care 4, 345-55. 

Spannheimer A, Clouth J, Gregor KJ (1999). Pharmacoeconomic evaluation of the rrearmenr of schizophrenia in Germany a comparison of olanzapine, risperidone and haloperidol using a clinical decision model. Poster presented at the ISPOR Second Annual European Meeting, Edinburgh, November 1999. 

Specific animal models are discussed in some detail in the appropriate chapters on epilepsy, depression, schizophrenia, etc. 

Geyer, MA, Swerdlow, NR, Mansbach, RS and Braff, DL (1990) Startle response models of sensorimotor gating and habituation deficits in schizophrenia. Brain Res. Bull. 25 485-498. 

The close resemblance between schizophrenia and PCP-induced psychosis suggests that the behavioral effects produced by PCP might be useful as a model of psychosis. On this basis, most animal studies have examined the ability of various agents to modify PCP-induced hyperactivity and stereotypy. While some studies suggest that neuroleptics such as haloperidol (Castellani and Adams 1981 Garey et al. 1980), chlorpromazine, or clozapine (Freed et al. 

Another crucial problem for any neurochemical model is cause and effect. Neuroleptics have a high affinity for dopamine receptors, particularly the D2-subtype. There is also a highly significant positive correlation (r > +0.9) between this receptor binding and their clinical potency (Seeman, 1980). But, this does not necessarily implicate elevated dopamine levels as the cause of schizophrenia. Moreover, blockade of dopamine receptors happens very rapidly, whereas clinical benefits are only seen after chronic treatment. Rose (1973) has criticised the reductionist statement that an abnormal biochemistry causes schizophrenia because it relates cause and effect at different organisational levels (namely, the molecular and behavioural). But, while it can be legitimate to discuss cause and effect at the same level that chlorpromazine blocks dopamine receptors (one molecule altering the response of another), it is not valid to infer that increased dopamine activity causes schizophrenia. Put another way ... 

Describe how the dopamine hyperactivity model for schizophrenia has changed and evolved over time. 

Figure 13.4 illustrates some of the factors known to be involved in the development of AD many of the known and putative links between factors are also shown. It should also be noted that the patterns of inter-factor modulation may be either positive or negative. However, it is clear that no single factor or combination of factors can explain all AD cases. It is best to conceptually model AD as a broad end point that can be reached in numerous ways. Similar multi-factorial models have been proposed for schizophrenia and depression (Chapters 11 and 12) and almost certainly underlie every other complex psychobiological concept. 

Diathesis stress model A multifactorial model of pathogenesis suggesting that schizophrenia is due to the complex interaction between a number of internal and external factors. 

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