Domains of dysfunction in schizophrenia: implications for diagnosis.

Psychiatry suffers from a paucity of molecular and cellular markers for its diseases. We do not have “measures” for diagnosis (like a hematocrit or a blood glucose) and therefore lack biological leads to pathophysiology of illness, critical for modern disease management. While knowledge of basic brain mechanisms is still incomplete, expectations still exist for a molecular and cellular pathophysiology in our diseases. Until we meet success with this goal, we have to be clever and insightful in using existing phenomenology and pharmacology to substantiate accurate diagnoses. From this perspective, the proposal raised by Richard Keefe, to include cognitive dysfunction in the diagnostic criteria for schizophrenia, is supported by our current knowledge and formulation of the illness. In addition to his argument that cognition adds a “point of rarity” for schizophrenia diagnoses, it is also true that amending the diagnosis to include cognitive dysfunction improves its accuracy as a base for proposing pathophysiology and new treatment. It is useful to consider what we can do to structure our clinical data to advantage progress in the molecular understanding of schizophrenia. Hyman and Fenton suggest that we can use “a clinical target, a well-defined risk state, illness or symptom complex for which treatment is meant… that can be monitored to test whether the drugs are effective” 1. Based on leadership from the National Institute of Mental Health, the field began doing exactly this, looking carefully at schizophrenia phenomenology to find distinctions between symp- tomatic domains. The analysis of large clinical data sets showed the correlation of groups of related symptom types across clinical course, organized into “domains” of dysfunction, specifically cognition, psychosis, negative symptoms and affect. The independence of these domains with respect to available treatments has become clear, especially for psychosis and cognition. Antipsychotics improve psychosis but do not treat cognitive dysfunction; the pharmacology of cognitive dysfunction is based on animal studies and supports the activity of drugs very different from antipsychotics, such as dopamine agonists, cholinergic drugs (nicotinic and muscarinic), and glutamatergic drugs 2. Thus, distinguishing between the process of psychosis and the development of cognitive dysfunction could bring a new clarity to pathophysiology. What are the domains of dysfunction in schizophrenia? The most frequently mentioned domains are positive symptoms (hallucinations, delusions and thought disorder), cognitive dysfunction (attention, working memory and episodic memory functions and processing speed), and negative symptoms (paucity of thought, lack of affect). These domains are independent with respect to clinical course and treatment. Whether they are independently associated with genetic or environmental risk factors has not been determined. Whether they are linked or independent with respect to pathophysiology remains a question. What is their relevance to pathophysiology? Whether these domains are entirely independent disease constructs or are related to each other, their pathophysiologies must be largely separable even if linked. Models of pathophysiology can best advance thinking if they are based on actual symptoms within a diagnosis. Thus, the disease definitions of schizophrenia and the domain constructs need to be related and valid. An attempt to develop a disease construct for “psychosis and cognitive dysfunction” may generate more successful hypotheses than a construct for “schizophrenia” and may lead to pathophysiologic models with greater disease validity. What is their relevance to treatment? It is widely accepted that treatments for psychosis and cognitive dysfunction will not be the same set of drugs. For psychosis, we have groups of well-validated antipsychotic drugs, the dopamine antagonists (direct and indirect). These drugs do not correct cognitive dysfunction, but effective cognitive enhancers have not yet been discovered. The concept of domain treatment will not only individualize treatment but will serve to optimize symptomatic treatments for each domain. Clinicians will need to distinguish the target symptoms for antipsychotic drugs and for cognition enhancers. In this situation, it would be not only reasonable but necessary that characteristics of cognitive dysfunction be part of the disease definition. From a practical perspective, how can cognitive dysfunction be assessed? It is important to consider whether and how treating physicians can gather and use cognition information. While at present “cognition dysfunction” comprises only vague characteristics of illness, there is no need for precise neuropsychological measurements. But, once we define the symptom domain and develop cognitive symptoms for treatment, then the situation will change. We will need the methodologies to assess and monitor cognitive symptoms. Therefore, there will be a critical need for practical approaches to cognition assessment, not only for diagnosis, but also for disease characterization and management. We will need cognition algorithms, developed by experts, for use by clinicians in making diagnoses and in measuring treatment outcomes. Since clinicians will be monitoring cognitive change once we have successful treatments, algorithms should be treatment-sensitive. Based on these considerations, should cognitive dysfunction be included in the diagnosis of schizophrenia? Given that cognitive dysfunction is now a recognized, relevant and nearly ubiquitous aspect of schizophrenia that will undoubtedly be important for disease understanding and for treatment success, the question almost answers itself. Moreover, this opinion reflects advances in our understanding of the illness that clinical assessment and research has brought to modern psychosis diagnosis. Keefe’s proposal that cognitive dysfunction be a criterion for schizophrenia is reasonable and should be implemented. It will remain for experts in the area to develop algorithms which are both simple and effective so that clinicians can implement the new perspective.