Heterogeneity of response to antipsychotics from multiple disorders in theschizophrenia spectrum

Background: Antipsychotic response after the initiation of neuroleptic trea tment shows wide variation in schizophrenic patient populations. In this ov erview, the authors suggest that the variance in antipsychotic drug respons e within schizophrenia can be reduced by resolving the schizophrenias into several discrete "endophenotypes," each with different etiologic underpinni ngs. Method: Studies relating differences in the relative speed or completeness of antipsychotic response to differences in distribution of 2 biological ma rkers with possible etiologic significance are reviewed. Such studies had a ssessed recently hospitalized, neuroleptic-free patients undergoing exacerb ation of nonaffective psychotic disorders. Prior to initiation of neurolept ic, the cohort of patients had been assessed fur the quantity of the dopami ne metabolite homovanillic acid in plasma (pHVA) and had undergone the firs t of 2 magnetic resonance imaging (MRI) studies for analyses of ventricle v olumes. A second MRI was subsequently performed during a period of (partial ) remission to determine within-patient stability of ventricular volumes. T hese selected studies assessed the distribution of pHVA and distribution of rates of ventricular change, with non-normal distributions resolved by K-m eans clustering. The speed and completeness of neuroleptic-induced antipsyc hotic response were related to 3 clusters of patients delineated by modal d istributions of pHVA and of apparent rates of ventricular change. Results: At least 3 unique "endophenotypes" of the "group of the schizophre nias" can be defined with respect to speed and completeness of antipsychoti c response. Each endophenotype appears to show at least one unique biologic al feature that differentiates it from a normal comparison group. A rapidly responsive psychosis was associated with excessive production of dopamine, as identifiable by elevation of pHVA and a "good-prognosis" course. A dela yed-response psychosis had low-to-normal pHVA, clinically demonstrated pers istent negative symptoms, and was associated with an excessive rate of chan ge in ventricle volume between exacerbations of psychosis and (partial) rem issions. Finally, a nonresponsive psychosis could be characterized as havin g both low-to-normal pHVA and rate of change of ventricle volumes similar t o that of controls. Additional studies revealed that each of the endophenot ypes had high rates of the psychoses in family members. The good-prognosis course of the rapidly responsive group of studied patients was also found i n their family members who had psychotic disorders. Similarly, the prominen t negative symp toms of the delayed-response probands were reflected as a p rominent trait in their family members also afflicted with psychosis. The e ndophenotypes tended to "breed true" in terms of prognosis and negative sym ptoms. Conclusion: Major differences in antipsychotic response patterns appear to be associated with patient and family characteristics that may be related t o differences in the etiology and consequent pathophysiology of illness.