Schizophrenia: Drug discovery

Drug discovery for schizophrenia has long been based upon the dopamine hypothesis resulting in many compounds with similar mechanisms of action and which provide relief of the hallucinations and delusions of the disease. Unfortunately these ‘antipsychotic’ drugs have limited effectiveness against the negative symptoms (such as reduced motivation) and cognitive deficits (such as impaired flexibility of thinking and working memory); symptoms which are especially associated with impaired functional outcome.

Several genetic risk factors for schizophrenia converge at the glutamate synapse and nucleus. Pratt et al (2012) Nature Reviews Drug Discovery 11, 560-579

More recently, the glutamate system has been implicated in schizophrenia. A specific subtype of the glutamate receptor, the NMDA receptor is thought to be critically important in brain circuits disrupted in schizophrenia. Emerging drug targets such as Glycine transport (GlyT1) inhibitors and metabotropic glutamate (mGlu2/3) receptor agonists are focussed on modulating NMDA receptor function and have been the subject of recent clinical trials. Unfortunately the results have been rather disappointing. Nevertheless researchers are now investigating whether previous antipsychotic drug experience may have limited the effectiveness of these ‘glutamate’-based drugs and also whether stratifying patients according to genetic risk factors may lead to improved results.

There still remains room for optimism for the ‘glutamate’ hypothesis of schizophrenia. In particular evidence from Genome Wide Association Studies (GWAS) of over 37,000 patients has identified genetic risk factors based upon the glutamate system and in parallel human imaging studies are identifying disturbed glutamate function. Such findings take us one step closer to identifying disease biomarkers.

Genetic and environmental risk factors are important in the causation of schizophrenia and psychiatric disorders in general. Understanding the neurobiology of the interaction of these factors and how this can impact on neurotransmitter function (such as glutamate), brain circuitry and behaviour is important for informing new drug discovery strategies and for the identification of biomarkers. Because genetic contributions to mental illness do not always map onto current diagnostic categories, the future is likely to be treatments for particular classes of symptoms that cross currently defined illness categories. Although moving at a slow pace, the vision at least for personalised medicines in neuropsychiatry is now on the horizon.

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