Cure therapeutics and strategic prevention: raising the bar for mental health research

Abstract

Mental disorders cause more disability than any other class of medical illness in Americans between ages 15 and 44 years. The suicide rate is higher than the annual mortality from homicide, AIDS, and most forms of cancer. In contrast to nearly all communicable and most non-communicable diseases, there is little evidence that the morbidity and mortality from mental disorders have changed in the past several decades. Mental health advocates, including psychiatric researchers, have pointed to stigma as one of the reasons for the lack of progress with mental illnesses relative to other medical illnesses. This review considers how the expectations and goals of the research community have contributed to this relative lack of progress. In contrast to researchers in cancer and heart disease who have sought cures and preventions, biological psychiatrists in both academia and industry have set their sights on incremental and marketable advances, such as drugs with fewer adverse effects. This essay argues for approaches that can lead to cures and strategies for prevention of schizophrenia and mood disorders.

Figure 1

Drug development in the past 50 years While pharmacologic research in cardiovascular medicine and other areas of medicine has developed medications with new mechanisms of action, psychiatry has enjoyed less innovation in terms of drug development. Over the past 50 years, new medications for schizophrenia and depression have been almost exclusively based on existing medications without developing compounds that have either new clinical targets (eg. the cognitive deficits in schizophrenia or suicidal behavior in depression) or new molecular mechanisms (beyond dopamine receptor blockade for schizophrenia or monoamine transporter or enzyme blockers for depression).

Figure 2

Pathways for drug development The traditional pathway for medication development in psychiatry has begun with a serendipitous clinical observation of efficacy followed by intensive study of the drug’s actions. Based on neuropharmacology, new drugs have been developed with greater specificity or potency and these, in turn, are tested in animal studies and clinical trials. This is a recipe for developing new drugs that will mimic existing drugs. The modern approach to drug development begins with identifying a molecular or cellular target based on pathophysiology, then uses high throughput screening of small molecule libraries to detect potential hits that can be refined by medicinal chemistry into drugs for testing in animals and ultimately adapted for clinical trials.