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.


Berry-Kravis EM, Hessl D, Coffey S, Hervey C, Schneider A et al.  2009. A pilot open-label single-dose trial of fenobam in adults with fragile X syndrome. J. Med. Genet.  (in press).

Canitano R. 2007. Epilepsy in autism spectrum disorders. Eur. Child Adolesc. Psychiatry 16:61-6.

Conn PJ, Lindsley CW, Jones CK. 2009. Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia. Trends Pharmacol. Sci. 30:25-31.

Crespi, B and Badcock, C 2008. Psychosis and autism as diametrical disorders of the social brain. Behav. Brain Sci. 31:241-261

Dölen G and Bear MF. 2008. Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome. J. Physiol. 586:1503-8.

Hagerman RJ, Berry-Kravis E, Kaufmann WE, Ono MY, Tartaglia N et al. 2009. Advances in the treatment of fragile X syndrome. Pediatrics 123:378-90.

Lippiello PM. 2006. Nicotinic cholinergic antagonists: a novel approach for the treatment of autism. Med. Hypotheses 66:985-90.

Mobascher A and Winterer G. 2008. The molecular and cellular neurobiology of nicotine abuse in schizophrenia. Pharmacopsychiatry 41 Suppl 1:S51-9.

Olincy A, Harris JG, Johnson LL, Pender V, Kongs S et al. 2006. Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch. Gen. Psychiatry 63:630-8.

Stevens JR. 1999. Epilepsy, schizophrenia, and the extended amygdala. Ann. N Y Acad Sci. 877:548-61.