Heterogeneity of Response to Antipsychotics From Multiple Disorders in the Schizophrenia Spectrum.

Background: Antipsychotic response after theinitiation of neuroleptic treatment shows wide variation inschizophrenic patient populations. In this overview, the authorssuggest that the variance in antipsychotic drug response withinschizophrenia can be reduced by resolving the schizophrenias intoseveral discrete “endophenotypes,” each with differentetiologic underpinnings.

Method: Studies relating differences in therelative speed or completeness of antipsychotic response todifferences in distribution of 2 biological markers with possibleetiologic significance are reviewed. Such studies had assessedrecently hospitalized, neuroleptic-free patients undergoingexacerbation of nonaffective psychotic disorders. Prior toinitiation of neuroleptic, the cohort of patients had beenassessed for the quantity of the dopamine metabolite homovanillicacid in plasma (pHVA) and had undergone the first of 2 magneticresonance imaging (MRI) studies for analyses of ventriclevolumes. A second MRI was subsequently performed during a periodof (partial) remission to determine within-patient stability ofventricular volumes. These selected studies assessed thedistribution of pHVA and distribution of rates of ventricularchange, with non-normal distributions resolved by K-meansclustering. The speed and completeness of neuroleptic-inducedantipsychotic response were related to 3 clusters of patientsdelineated by modal distributions of pHVA and of apparent ratesof ventricular change.

Results: At least 3 unique”endophenotypes” of the “group of theschizophrenias” can be defined with respect to speed andcompleteness of antipsychotic response. Each endophenotypeappears to show at least one unique biological feature thatdifferentiates it from a normal comparison group. A rapidlyresponsive psychosis was associated with excessive production ofdopamine, as identifiable by elevation of pHVA and a”good-prognosis” course. A delayed-response psychosishad low-to-normal pHVA, clinically demonstrated persistentnegative symptoms, and was associated with an excessive rate ofchange in ventricle volume between exacerbations of psychosis and(partial) remissions. Finally, a nonresponsive psychosis could becharacterized as having both low-to-normal pHVA and rate ofchange of ventricle volumes similar to that of controls.Additional studies revealed that each of the endophenotypes hadhigh rates of the psychoses in family members. The good-prognosiscourse of the rapidly responsive group of studied patients wasalso found in their family members who had psychotic disorders.Similarly, the prominent negative symptoms of thedelayed-response probands were reflected as a prominent trait intheir family members also afflicted with psychosis. Theendophenotypes tended to “breed true” in terms ofprognosis and negative symptoms.

Conclusion: Major differences in antipsychoticresponse patterns appear to be associated with patient and familycharacteristics that may be related to differences in theetiology and consequent pathophysiology of illness.