The Grand Challenge of Schizophrenia Drugs

A milestone for Big Neuroscience came Wednesday with the publication in Nature of a study on the way genes switch on across the whole human brain.

Whole brain is all the vogue.

Neuroscientists have devoted inordinate energy in recent years to publicize  the need for, not only gene maps, but for a full wiring diagram of all brain circuits. The benefits of a connectome as it is known might yield new understanding that could eventually result in  pharmaceuticals for intractable psychiatric disorders. This ultimate neural network might even divvy up intimations of the workings of consciousness.

The futurist contingent, many of whom began careers hacking computers not neural circuity, has speculated that a whole brain blueprint of you or me might be copied to a hard drive so that we can live for a digital eternity like Max Headroom. Christof Koch, the chief scientist at the Allen Institute for Brain Science, the organization that produced the gene map, dismissed  facile optimism about the prospects for these scenarios with a commentary in Science last month. In it,  he calculated that it could take 2000 years to analyze all of the possible interactions among the 1,000 different proteins that populate  a single synapse. Koch then went on to speculate about a way of reducing the complexity of such calculations.

The question still remains of how we will know when we have actually started to make sense of the tangle of wiring that populates the deepest recesses inside our skulls.  One plausible answer: when the FDA approves a new drug that fundamentally advances treatment of schizophrenia, the psychiatric illness that has aberrant effects on a multitude of neural pathways—an iconic example of the brain’s underlying complexity.

Steven Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute— his CV includes stints as provost of Harvard and director of the National Institute of Mental Health—just wrote a review and analysis piece for Nature Neuroscience that lays out through a specific example the challenge of new schizophrenic drugs in the c0ntext of intricate brain circuitry gone awry. Existing drugs have limited effectiveness.

Hyman looks at a study published in the same issue of the journal that describes a possible new approach to treating schizophrenia, one that brings to bear the trendy sub-discipline of epigenetics— changing  the way genes get switched on or off without any alteration to the underlying DNA. The article describes an experiment that demonstrates the way that the latest generation of antipsychotic drugs are less effective than they could be because  over time, they turn off a gene that helps reduce symptoms of psychosis. The diminishing performance of the antipsychotics appears to result from an epigenetic mechanism that removes a  chemical tag, an acetyl group, that turns off the gene in question, raising the possibility that another drug might be developed one day to counteract this effect.

Hyman praises the work of the collaboration led by researchers from Mt. Sinai School of Medicine in New York as “rigorously performed and informative.” He then adds that it may be difficult to translate this experiment into an actual drug without understanding better the complex nature of schizophrenia (think circuit diagrams) and without improved methods of testing new drugs before they go into human trials. Anti-psychotic drugs were among the biggest profit earners for drug companies in the last decade despite their shortcomings. Yet new development on next-generation anti-psychotics has stalled and most companies have greatly scaled back or abandoned their efforts—”…the scientific hurdles currently seem too high,” Hyman laments.

One hitch is the way new treatments get tested in rodents. Researchers often attempt to mimic schizophrenia by just dosing a mouse with a hallucinogen, which, as Hyman notes, has “no clear relationship to underlying mechanisms of schizophrenia.” The only way forward may be to “use genetic results—and reproducible results are finally emerging for schizophrenia—to identify a handful of pathways involved in pathogenesis.” The disease pathways then need to be simulated some way in a mouse to elicit both genetic and epigenetic mechanisms involved with schizophrenia. Rodents may not serve for all the needed studies because of the gaping evolutionary gap between humans and mice—testing of neurons in a laboratory dish may have to suffice. Only if these elements can be assembled and made to work will it then be possible to contemplate a new era of drug development that proceeds from circuit diagram to circuit repair.