Models of the Possible Biological-Genetic Relationships Between Clinical Phenotypes on a 1-Dimensional Schizophrenia-Bipolar Disorder Clinical Spectrum. Each circle/ellipse denotes that a particular set of genes (which index associated proteins and biological pathways involved in that phenotype—“disease processes”) influence a range of clinical phenotypes within that part of the clinical spectrum and that further differentiation of the disease process-clinical phenotype relationship is not possible. The models are presented in order of their complexity from a single psychosis disease entity without any phenotypic structure through models with increasing numbers of biologically distinct clinical entities to a phenotypically structured continuum that represents the limit of an increasing number of biologically distinct clinical entities. Current data allow rejection of the first 2 models. The other models are possible and require testing against empirical data.

Simplified Representation of the Clinical Functional Psychosis Spectrum to Demonstrate the Problems if a Classification Fails to Facilitate Grouping Together Cases With Similar Clinical Features and Biological Predisposition. Below the solid double-headed arrow is a notional representation of a 1-dimensional spectrum of clinical features from “prototypical schizophrenia” on the left through “schizoaffective” to “prototypical mood disorder” on the right. Between the 2 sets of colored boxes, we show diagnostic categories and the locations of 5 individuals, A, B, C, X, and Y, on the clinical spectrum. The lower set of colored boxes correspond to current Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) diagnostic concepts; SA designates DSM-IV schizoaffective disorder. In the upper set of boxes, diagnostic categories correspond to an alternative scheme in which the commonly occurring “middle ground,” “mixed,” or “broad schizoaffective” category is accorded greater status and extends over a wider part of the middle of the spectrum than does the very restrictive DSM-IV definition. Individuals A, B, and C have similar clinical features but under DSM-IV are assigned to different categories. Further, individuals X and A are placed in the same category even though A shares much less in common with X than with B. (A similar argument holds for B and Y.) Given that there is evidence to support the existence of some degree of genetic specificity toward the phenotypes expressed by cases A and B, the current situation is extremely unhelpful to research and practice. It can be seen that broadening the concept of “schizoaffective” is one simple way of improving the appropriate recognition of the similarity of these cases. Of course, such a “trichotomy,” while an improvement over the dichotomy, is still associated with the problems inherent in setting boundaries between categories. Approaches involving dimensional measures may be preferable, but the key conceptual point is facilitating recognition and grouping together of such cases and making clinicians and researchers abandon dichotomous thinking.

Example of a 3-Dimensional Representation of Some Key Clinical Domains of Functional Psychosis Showing How Current Diagnostic Categories Are Related to Dimensional Scores. This is illustrative, and we can expect that more dimensions will be necessary to capture the biologically relevant clinical variation. Determining the most useful dimensional measures will be an iterative process requiring substantial work on both the biological underpinnings of illness and the measurement of the phenotype (which will include clinical characteristics as well as measures of psychological functioning). This simple 3-dimensional representation is based on 3 dimensions from our descriptive scale, the Bipolar Affective Disorder Dimension Scale.77 It can be seen that current diagnostic categories map to different parts of the 3-dimensional space. Thus, all information contained within a current diagnostic category is included, but the approach provides substantial additional information that provides a better characterization of the individual's illness. BP: bipolar disorder; SA, BP: schizoaffective disorder, bipolar type; SA, Dep: schizoaffective disorder, depressive type.