Diagnostic Categories: Provisional, Not Otherwise Classified, or Place-holder? (2024)

Diagnostic class for persons who merit clinical care is often uncertain, especially early in the course of illness. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), eg, provides “provisional” when the clinician thinks a particular disorder is present but realizes more information is required to be confident of a specific diagnosis. Similarly, other specified and unspecified disorders enable the clinician to designate a diagnostic class specifying why data is inadequate to meet full criteria or to choose no explanation. These approaches to uncertainty in clinical practice permit selection of a diagnosis with code with or without explanation. But this method of addressing diagnostic uncertainty does not facilitate acquisition of generalizable knowledge. Cases with these diagnoses are usually excluded from clinical trials and evidence-based interventions are not available. Consider the dearth of therapeutic information on brief psychotic disorder or schizophreniform disorder.

Categories for established disorders such as bipolar or schizophrenia are expected to be stable over time and recent meta-analyses have relatively good diagnostic stability for schizophrenia, rather good for bipolar disorder, and less satisfactory for schizoaffective disorder.^1,2 But lack of stability may simply reflect clarification over time with course data rather than challenging the validity of the diagnostic class. This is surely the case when diagnostic change is within the same psychopathology spectrum. Moving from schizoaffective to schizophrenia overtime may represent greater affect pathology in early course of schizophrenia. But an initial schizoaffective disorder diagnosis in a person with bipolar disorder may be associated with suboptimal therapeutics early in the course of illness.

With rapidly growing attention to early detection and intervention related to schizophrenia spectrum, bipolar and major depression disorders a new diagnostic challenge emerges.^3,4 The approaches to diagnosis noted above may provide a diagnostic code useful in clinical practice, but these provisional and uncertain diagnostic categories are not useful in the acquisition of knowledge. Scientific advance is dependent on meaningful patients/participants cohorts. We have advocated elsewhere for the concept of place-holder diagnoses to address this need in relation to the clinical high risk studies relevant to the schizophrenia prodrome^5,6 and this has been debated.⁷ The concept of “place-holder” in this context is 2-fold. First is to enable investigation of a meaningful cohort of individuals manifesting specified psychopathology that is not adequately addressed by existing diagnostic categories. Second is to enable translation of research to individuals in clinical care by clarifying to whom research findings generalize. Uncertainty as to the later diagnostic outcome is explicit, but so are the inclusion and exclusion criteria used in defining the category.

Attenuated psychosis syndrome (APS) in Section 3 of DSM-5 is a good example. APS is based on the proposition that persons at increased risk for developing a psychosis within the schizophrenia spectrum can be identified at a stage where psychopathology merits clinical attention but full psychosis had not developed. Various clinical high risk criteria have been used in expert centers and data support the need for clinical care for symptoms and dysfunction already present.⁵ The clinical high risk patients transition to full psychosis at a substantial rate, but the majority do not develop a psychotic disorder. A provisional specifier for schizophrenia would be incorrect in most cases and the use of not otherwise specified (NOS) would be uninformative for research purposes. What is needed is a clinical diagnosis that simultaneously captures the manifest psychopathology, associated dysfunction, and elevated risk for full psychosis. This has been successfully implemented at many expert centers with good reliability and validity and it has proven useful in research ranging from biomarkers to clinical trials.^5,8,9 It is explicit in place-holder status with a range of clinical outcomes expected and with secondary prevention of psychosis applicable to a subset. Having diagnostic categories relating to clinical high risk concepts for various disorders provides a critical aspect of methodology for investigating early detection and therapeutic interventions for current symptoms and functional impairments and secondary and tertiary prevention for cases that might otherwise progress to a more serious diagnostic category. If such a category is essential for scientific exploration it follows that the category must be applied in clinical care to translate research into evidence-based clinical care. Guidelines are already being introduced.¹⁰

Such place-holder diagnoses may also advance our understanding of the interface between vulnerability and manifest psychopathology. Examples in the DSM-IV Appendix for further research include Pre-menstrual Dysphoric Disorder (PMDD) and Binge Eating Disorder (BED). Although neither diagnosis was considered adequately studied for inclusion as official diagnoses in the early 1990s, the availability of explicit diagnostic criteria for these conditions facilitated clinical trials for PMDD and prevalence estimates and preliminary trials for BED that led to their inclusion as official diagnoses in the DSM-5. The results of trials for PMDD were sufficiently strong for the FDA to grant an “indication” for the use of fluoxetine for this condition—even before its official recognition in DSM-5.

For APS and some of the other DSM-5 Section 3 diagnoses for further research, much is known regarding environmental and genetic risk factors, but primary prevention has been difficult to implement when conceptualized as prevention of a specific and fully manifest disorder. Prevention of vulnerability and transition from vulnerability to early psychopathology may be the optimal targets for prevention in the field of psychoses and related disorders. Place-holder diagnostic categories may be considered intermediate between vulnerability and fully manifest psychopathology. As such, they may be essential in understanding the various pathways to mental disorders and define targets for primary prevention.

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