Antipsychotics and antidementia agents

In a neuroscience lecture this morning given by James Reed of Birmingham and Solihul Mental Health Foundation Trust, we followed the progress of a number of "typical" mental health, including schizophrenia and Alzheimer's disease cases. One interesting point I noted was that in both cases there was administration of drugs (anti-pyschotics in the schizophrenia case and drugs such as donepezil ("Aricept") in the Alzheimer's case). I feel there is something to be learned for my research from how antipyschotics and antidementia agents act on the brain to reduce the symptoms. It's clear in both cases that the drugs do not address the causes of the disorders, but only manage the symptoms of the suffers. A bit of Wikipedia trawling follows... (proper paper references to come when I properly research this!)

Aricept is a type of acetylcholinesterase inhibitor (i.e. it inhibits the enzyme which breaks down acetylcholine), which ties in with the theories I've read in Stein and Ludik (1998) about the role of acetylcholine in memory management and prevention of runaway synaptic modification. The Alzheimer's Society helpfully explain that "Aricept, Exelon and Reminyl prevent an enzyme known as acetylcholinesterase from breaking down acetylcholine in the brain. Increased concentrations of acetylcholine lead to increased communication between the nerve cells that use acetylcholine as a chemical messenger, which may in turn temporarily improve or stabilise the symptoms of Alzheimer's disease ... the action of Ebixa is quite different to, and more complex than, that of Aricept, Exelon and Reminyl. Ebixa blocks a messenger chemical known as glutamate. Glutamate is released in excessive amounts when brain cells are damaged by Alzheimer's disease, and this causes the brain cells to be damaged further. Ebixa can protect brain cells by blocking this release of excess glutamate."

Most antipyschotic drugs appear to work by simply blocking dopamine receptors in the brain, typically the D2 or D4 receptor, and "atypical" antipsychotics also act on serotonin receptors. James mentioned that clozapine is a particularly effective antipsychotic (although it is rarely used now as it has some severe side-effects), and no-one quite knows why, although apparently it acts on D2 less strongly than other antipsychotics. Developing a new drug which works in the same way, but without the side-effects, is a major part of clinical schizophrenia research which would be aided by knowing how clozapine actually works, and how it is different to other antipsychotics! This is potentially something I could attempt to model during my work.

There is some interesting background to various medical and neurological theories about the causes of schizophrenia on Wikipedia too, with particular mention of the Glutamate (related to NMDA receptors; see Greenstein and Ruppin, 1998) and Dopamine (supported by the fact that antipsychotics work by blocking dopamine receptors) theories. Apparently the glutamate hypothesis "does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models." (Lisman et al., 2008, as cited at Wikipedia).

Interestingly, glutamate is mentioned in both schizophrenia and Alzheimer's disease, although for different reasons. In the glutamate theory of schizophrenia (non-Wikipedia link), treatment is performed by increasing the amount of glutamate available, whereas Ebixa attempts to reduce the amount of damage caused by glutamate in Alzheimer's disease.

Finally, the BBC has produced a Dementia 2010 news feature focussing on dementia and Alzheimer's disease. Of particular interest, if only for soundbites as part of my introduction, are:

• Dementia 'losing out' to cancer in funding stakes (The usual sob story, albeit justified, calling for more funding).
• What is delaying a cure for Alzheimer's? (The answer again is "funding", but the article at least acknowledges that much of the currently-reported Alzheimer's disease research progress in the media simply focusses on seemingly trivial findings, such as that eating cornflakes three times a day and tying your shoelaces immediately before attempting a crossword statistically lowers your chances of developing AD, without going deeper into why).
• Indian village may hold key to beating dementia (Nearly one of the aforementioned "trivial observations" reports, but at least they did some research into more specific factors such as a low-cholesterol, vegetarian diet, and lack of the APO4E gene which apparently predisposes people to AD. This also links to a paper by Sima and Li (2006) on a proposed connection between diabetes and Alzheimer's disease).

References
Greenstein-Messica, A. and Ruppin, E. (1998), "Synaptic runaway in associative networks and the pathogenesis of schizophrenia", in Neural Computation 10:451--465.

Lisman JE, Coyle JT, Green RW, et al. (May 2008). "Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia". Trends in Neurosciences 31 (5): 234–42.

Sima, A.A.F and Li, Z. (2006), "Diabetes and Alzheimer's Disease - Is There a Connection?". The Review of Diabetic Studies 3(4):161.


Stein, D.J. and Ludik, J. (1998), Neural Networks and Pyschopathology, Cambridge University Press.