Pharmacogenomics, informatics, and individual drug therapy in psychiatry: past, present and future.

The modern era of psychopharmacology began in the 10 year period from the late 1940s to the late 1950s. During this period, the first antidepressants, antipsychotics, anxiolytics and mood stabilizers were all discovered. In the 1960s, the pharmacology of these drugs was elucidated and theories about the mechanisms of action proposed. In the 1970s and 1980s, new, more selective compounds were developed based on improved structure-activity relationships derived from in vitro receptor binding studies and animal models. These compounds entered clinical testing in the 1980s and began to be marketed in the late 1980s and 1990s. All of these agents were approved to treat psychiatric syndromes which are conditions defined by a cluster of signs and symptoms. None of these agents was developed based on an understanding of the pathophysiology of the illnesses being treated. None of these agents are curative and virtually all have limited clinical efficacy. In the earliest days of the modern era, there were few drugs available to combine and many had such broad actions that they were often marginally tolerated or unsafe when used in combination (tricyclic antidepressants and monoamine oxidase inhibitors). With the advent of more medications, the frequency and extent of polypharmacy has exploded. In addition to simply having more drugs from which to select with different pharmacological profiles, many newer medications are also more selective in their pharmacological actions and thus are often better tolerated and safer when used in combination. In addition, there is the concern that the trade-off for more selective pharmacology may have been better tolerability at the expense of reduced efficacy, which clinicians then compensate for by using more medications in combination. For all of the above reasons, polypsychopharmacology has been present from the beginning of the modern era of psychopharmacotherapy and continues to be the rule rather than the exception. In fact, the frequency and the complexity of such polypsychopharmacology are both enormous and increasing. The percentage of patients being discharged from the Biological Branch of the National Institute of Mental Health on more than three psychiatric medications increased more than ten times between 1974-79, and 1990-95. The majority of patients seen in the Veterans Administration Medical System in the United States are on unique combinations of medications and the frequency and complexity of such polypharmacotherapy is increased in patients on psychiatric medications. Throughout the modern era, there have been attempts to determine whether there are populations of patients selectively responsible to specific agents (e.g. serotonin versus norepinephrine reuptake inhibitors). However, no compelling data have so far emerged. Instead, clinicians generally resort to combining drugs on the basis of symptoms such as psychosis and depression or anxiety and depression. Science has primarily informed the clinician about safety concerns rather than efficacy concerns when using such combinations. That will change in the future with a better understanding of the pathophysiology of psychiatric illnesses which in turn will lead to improved therapies and the potential for more rationally derived combination treatments.