Towards a clinical methodology for neuropsychopharmacological research.

Neuropsychopharmacology is dedicated to the study of the pathophysiology and treatment of mental pathology with the employment of centrally acting drugs. In neuropsychopharmacological research the clinical effects of a psychotropic drug are linked to the effects of the substance on brain structures involved in its mode of action. It is assumed, that knowledge about the mode of action of a selectively effective psychotropic drug will provide clues about the pathophysiology of the illness, and conversely, that knowledge about the pathophysiology of an illness, will provide clues for developing clinically more effective psychotropic drugs. Since the currently employed clinical methodology for the demonstration of therapeutic efficacy links the mode of action of psychotropic drugs to pharmacologically heterogeneous populations, neuropsychopharmacological research does not provide the necessary feedback for developing more effective drugs. To resolve the pharmacological heterogeneity within currently used diagnoses, attempts were made to split syndrome-based psychiatric diagnoses into discrete neurobiological deficits, and to replace traditional psychiatric nosology by a genetic psychiatric nosology. Yet, to date, there is no alternative methodology to psychopathology-based psychiatric nosology for classifying mental pathology in a clinically relevant manner. As we are moving from the "neurotransmitter era" to a "genetic era" in neuropsychopharmacology, the need for identifying pharmacologically homogenous populations is becoming imminent. All primary targets of psychotropic drugs in the brain are encoded by genes which are identified, and any nosologic entity or psychiatric syndrome that corresponds with a treatment responsive population is a candidate for the generation of genetic hypotheses relevant to mental illness. Recognition that progress in neuropsychopharmacology, and molecular genetic research, depends on the speed clinical research can resolve the pharmacological heterogeneity within currently used diagnoses, led to the development of methodologies for the identification of treatment responsive form(s) of illness, such as the Composite Diagnostic Evaluation (CODE) System, and nosologic homotyping. The CODE System is a methodology for the identification of treatment responsive forms of illness if covered up by consensus-based diagnoses; it consists of a set of diagnostic algorithms that can assign simultaneously a diagnosis from several classifications to a patient. Nosologic homotypes are identical in elementary units of mental illness and are assigned the same position in the nosologic matrix, based on three "nosologic organizing principles. The empirically derived diagnostic categories are suitable for testing hypotheses relevant to the relationship between the "processing of mental events" and "signal transduction" in the central nervous system.