Soon after antipsychotics entered the market in the 1950s, policymakers were so impressed with their benefits that they felt they could let many patients out of the institutions they had been living in for years, sometimes decades. The drugs were clearly revolutionary, and effective at treating the positive symptoms - hallucinations, paranoid delusions - of schizophrenia, but it soon became apparent that they were largely ineffective at mitigating the negative symptoms such as depression and cognitive defects. It also became clear that they had serious side effects, from stiffness to outright tardive dyskinesia, because of the fact that they targeted dopamine 2 (D2) receptors.

That unmet medical need fueled decades of research. Some of it, detailed on these charts, produced variations on the original "typical" dopamine antagonists, with varying effectiveness and side effect profiles. Then, in the late 1980s, clozapine made an entrance, with its approval as the first "atypical" antipsychotic. Clozapine, which targets all five dopamine receptors and also has affinity for serotonergic receptors, showed promise in treating not only the positive symptoms, but the negative symptoms as well. But it caused agranulocytosis in some patients - a risk that could be mitigated, but still made some psychiatrists nervous, limiting its use.

So the search continued for atypicals. The 1990s saw the introduction of risperidone and olanzapine, among others. All seemed to be more effective than older typical drugs, but the honeymoon ended after a while. The drugs turned out to have some of the same side effects as the older drugs, although at a lower frequency in many cases. But they also had other important side effects, in particular weight gain and diabetes. They were also quite expensive, and remain more expensive than the older drugs. So when the CATIE trial came along, many psychiatrists wondered what the newer drugs were offering.

Some doctors are doing what they can to mitigate the side effects of many of these medications, by trying lower doses and adding other drugs such as antidepressants to boost their effectiveness. But better drugs are still needed. In this chart, we highlight examples of some of the promising drug candidates, which act at receptors including dopamine, serotonin, and glycine. You can also read about NMDA, a receptor whose potential is exciting a number of researchers and driving many efforts. This is just one of the many threads of schizophrenia research that makes the subject so timely.