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///////////////The Dawn of Darwinian Psychopharmacology
Feb 5th, 2009 by Bernard Crespi
We usually consider medicine as a predictive scientific endeavor, as methodical in application as noble in purpose. But for some diseases, such as schizophrenia, the first treatments showing any effectiveness, including lithium, chlorpromazine, and even electroconvulsive therapy, were discovered entirely by accident. After the discovery of the first antipsychotic treatments, a period of allegedly rational schizophrenia drug development ensued, focusing on drugs that block the brain dopamine receptor DRD2 that was considered, based on very limited evidence, as the critical lock for chemical antipsychotic keys. Some of the drugs worked - more or less, with serious side effects. Truly rational drug development, however, required understanding of the causal basis of disease, which for brain diseases like schizophrenia requires, to a considerable extent, understanding the dark inner workings of the brain itself.
But the causal basis of one relatively-simple brain disease, Fragile X syndrome, has, in the past few months, been deciphered - a true milestone in the touted medical march from brain to computer, lab bench to bedside. Afflicting about 1 in 3000 children, Fragile X is the most-common known cause of both intellectual disability and autism. A series of studies, led by researchers including Gul Dölen and Mark Bear at MIT (Dölen and Bear 2008) and Randi Hagerman at UC Davis (Hagerman et al. 2009), has identified the core neuronal defect caused by mutation of the fragile X gene, and shown they can fix it - literally cure it (Figure 1) - in mice. The fix involves reducing the expression or activity of a metabotropic glutamate receptor 5 (mGluR5), via genetic modifications, and apparently, by treatment with drugs that antagonize the mGluR5 receptor. Human trials with mGlur5 antagonists are ongoing, with good early results (Berry-Kravis et al. 2009), and hope for the first effective treatments for the causes of autism itself, and not just alleviation of symptoms.
All very rational. In parallel and quite independently, biochemists and pharmacologists studying schizophrenia have converged on a central role for glutamate receptor alterations as causes of schizophrenia. These workers have - quite scientifically rather than serendipitously - developed a new class of drugs that are highly effective as antipsychotics in animal systems (Conn et al. 2009). One of the most promising: agonists of mGlur5 - drugs with the same precise target, but opposite effects, as the mGlur5 antagonists that may cure the autistic disorder Fragile X.
Coincidence? Perhaps, but a second novel class of drugs being developed for schizophrenia is agonists of the a7 nicotinic receptor - the receptor that schizophrenics self-stimulate via their extraordinarily high rates of cigarette smoking (Mobascher and Winterer 2008). And again quite independently, antagonists of the same receptor have been proposed as therapeutic agents for autism, based on a diversity of evidence (Lippiello 2006).
A look back to the first effective schizophrenia therapy, induction of seizures via electroshock, suggests a third contrast between schizophrenia and autism: seizures occur normally at very high rates (25-30%) in autistics (Canitano 2007), and most anti-psychotics in current use, including clozapine, tend to lower the threshold for seizures to occur (Stevens 1999).
Why should blocking a brain receptor alleviate autism, while activating the same receptor improves symptoms of schizophrenia?
Why should inducing seizures help schizophrenics, while reducing seizures is integral to helping autistics? From an evolutionary perspective, these two conditions can be seen as opposites, with the social brain under-developed in autism but hyper-developed to dysfunction in schizophrenia, and such diametric social-brain alterations are underpinned by diametric neurological, biochemical and genetic perturbations (Crespi and Badcock 2008). Methodical, predictive application of such an evolutionary perspective should provide a useful and rational framework to develop future therapeutics for both autism and schizophrenia, and hasten the dawn of Darwinian psychopharmacology.
////////////////In short: autism and schizophrenia represent opposite ends of a spectrum that includes most, if not all, psychiatric and developmental brain disorders. The theory has no use for psychiatry’s many separate categories for disorders, and it would give genetic findings an entirely new dimension.
“The empirical implications are absolutely huge,” Dr. Crespi said in a phone interview. “If you get a gene linked to autism, for instance, you’d want to look at that same gene for schizophrenia; if it’s a social brain gene, then it would be expected to have opposite effects on these disorders, whether gene expression was turned up or turned down.”
/////////////////Those with the genetic disorder called Angelman syndrome typically have a jerky gait, appear unusually happy and have difficulty communicating. Those born with a genetic problem known as Prader-Willi syndrome often are placid, compliant and as youngsters low maintenance.
Yet these two disorders, which turn up in about one of 10,000 newborns, stem from disruptions of the same genetic region on chromosome 15. If the father’s genes dominate in this location, the child develops Angelman syndrome; if the mother’s do, the result is Prader-Willi syndrome, as Dr. Haig and others have noted. The former is associated with autism, and the latter with mood problems and psychosis later on — just as the new theory predicts.
Emotional problems like depression, anxiety and bipolar disorder, seen through this lens, appear on Mom’s side of the teeter-totter, with schizophrenia, while Asperger’s syndrome and other social deficits are on Dad’s.
/////////////////////But experts familiar with their theory say that the two scientists have, at minimum, infused the field with a shot of needed imagination and demonstrated the power of thinking outside the gene. For just as a gene can carry a mark from its parent of origin, so it can be imprinted by that parent’s own experience.
The study of such markers should have a “significant impact on our understanding of mental health conditions,” said Dr. Bhismadev Chakrabarti, of the Autism Research Center at the University of Cambridge, “as, in some ways, they represent the first environmental influence on the expression of the genes.”
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