The dialectic tension of Emil Kraepelin defining dementia praecox [schizophrenia] as a single disease entity comprising two maladies, and Eugen Bleuler suggesting a heterogeneous syndrome [the group of schizophrenias] while asserting that the fundamental dissociative pathology was present in all cases. This early 20^th century dilemma was made lively by the assertion that precise attention to nuclear symptoms [Schneider's first rank symptoms, Langfeldt's true schizophrenia] resulted in a disease entity validated by increased homogeneity in onset, symptoms, and course. It was at this juncture that our early analyses rejected the nuclear schizophrenia hypothesis, defined separable components of pathology associated with schizophrenia [positive psychosis, negative symptoms, and social pathology].

  What would you rate as your most difficult or trying professional moment?

From a clinical perspective, it is the continuing disappointment in finding therapeutic interventions which robustly affect the course of cognitive impairments and primary negative symptoms; the general failure to remarkably better the functional outcomes and quality of life of our patients.

From a scientific perspective, it has been the slow pace of change in scientific designs to shift from the single disease entity paradigm to the study of more discrete pathologic entities identified within the schizophrenia syndrome.

From an ethics and public information perspective, it has been the substitution of acrimony and false allegation for constructive evolution of high standards for the ethical conduct of psychiatric research.

  Which of your professional achievements brings you the most satisfaction?

Most gratifying on a daily basis is the development of the Maryland Psychiatric Research Center as a rich and intimate personal context for basic and clinical neuroscientists to learn, work, and produce new knowledge.

As a clinician, there is immense satisfaction in developing innovative clinical care for patients who suffer from perhaps the worst disease afflicting the human race.

As a scientist, it is the belief that having contributed to identifying the aspects of schizophrenia which are not responsive to current therapies increases the probability of discovery that will make a more decisive improvement in the life of persons with schizophrenia.

  What impact might your work and research advances in your field have on the general public?

  Did you expect your work to become highly cited, or is this surprising to you?

Early in the work, it seemed interesting because it caused such intense reaction from advocates of the nuclear schizophrenia/one disease paradigm. It was much later that a sense of the importance of a shift in paradigm was appreciated and implications were far beyond course and diagnostic issues. But it still is surprising, since most study designs are single-disease oriented, most negative symptom reports fail to distinguish primary from secondary, trait from state pathology; and most treatment development is aimed at psychosis as though a better antipsychotic would address the elements of schizophrenia not addressed by drug development to date.

  What lessons would you draw from your work to pass on to the next generation of researchers?

Two things:

1. Many reports of descriptive relationships would have been more decisive if conducted and reported in a strong inference, theoretically important, hypothesis falsification framework. Schizophrenia research still reports thousands of associations between variables, but few studies force theory modification with hypothesis rejection.

2. The problem of experimental group heterogeneity is present in most studies of schizophrenia, and is generally not addressed. Our work has provided a robust reduction in heterogeneity [deficit schizophrenia vs. nondeficit schizophrenia] validated at many levels of function [e.g., neuropathology through pharmacologic response]. This is illustrative of the validity of reducing heterogeneity, and researchers have several tools which can be applied in experimental design.

  If you had the power to make a single, sweeping change in the way that scientific research is conducted and presented, what would it be?

Inculcation of the following elements in research design:

1. Specify hypothesis where results could modify an important theory;
2. Relate hypothesis to specific element of schizophrenia [rather than to the syndrome];
3. Assure that experimental subjects actually have the element of pathology being studied; and
4. Assure that the comparison group reduces chance of artifact findings [e.g., within schizophrenia comparisons, control group with neuroleptic exposure].

The reason is to overcome the predominant mode of research, which is to report descriptive findings in experimental groups where subjects are ascertained for syndrome status rather than specific pathology, and where neuroleptic and other artifacts may account for between-group differences on dependent variables. An example is a study purporting to test a negative symptom hypothesis where experimental subjects are not ascertained for primary negative symptoms. Or where post-mortem tissue from suicide cases is used to test a hypothesis related to negative symptoms [but negative symptoms could not be ascertained and patients with deficit {primary negative pathology} are at reduced risk compared to nondeficit schizophrenia] for suicide.

  Would you like to leave any other comments about your work or share a personal side of yourself to be included in the piece?

Schizophrenia research is a wonderful mission that combines idealism [for those with a passion to improve the plight of those who suffer from this terrible brain disease] with the intellectual challenge of brain science and human behavior in the context of exciting and dedicated colleagues. For me, this has been a fantastic way to live a work life: learning new things daily among people I cherish.