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Parsing schizophrenia

The effective treatment of schizophrenia has long presented a challenge to clinicians and scientists. Common misunderstandings around symptoms and behaviors, and inadequate approaches to diagnosis and physiology, have hindered significant progress for patients and professionals. However, with recent advances in both methodology and research, it might be possible to design specific treatment regimens to address the various forms of the illness. Personalized medicine for the individual with schizophrenia is on the horizon.

The concept of schizophrenia began over a hundred years ago when Emil Kraepelin defined two major psychoses: manic-depressive psychosis (now termed bipolar disorder) and dementia praecox, a disorder comprising disorganization of thought and avolition pathologies with a chronic course. Eugen Blueler coined the term schizophrenia, emphasizing the concept of “splitting” or schism–the dissociation within thought and between thought, emotion, and behavior. To differentiate schizophrenia from other forms of psychosis, Kurt Schneider provided first rank symptoms for diagnosis and shifted the concept towards a reality distortion disorder based on special forms of hallucinations and delusions.

Despite the clarity with which these pioneers defined schizophrenia, there are two major impediments to further scientific enquiry. First, schizophrenia is a heterogeneous clinical syndrome: a grouping of patients with important similarities in the absence of known causal pathways. (Dementia, for example, is a syndrome where the memory impairment is central but can be caused by distinct diseases such as Alzheimer’s or stroke.) Second, the various pathologies associated with the syndrome are not unique to schizophrenia.

Scientists and clinicians have been slow in addressing the problems associated with a heterogeneous clinical syndrome. There are noteworthy exceptions, but even today most genetic studies are based on schizophrenia as a phenotype, regulatory bodies approve drugs for the syndrome, and most scientific studies are designed as though schizophrenia is a single disease entity rather than a syndrome.

However, the most recent edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) introduced eight symptom dimensions to be assessed in patients with psychotic disorders. Deconstructing the syndrome into these component domains of psychopathology provides more discreet targets for causal and therapeutic discovery. While antipsychotic drugs are approved for schizophrenia by regulatory bodies, the scope of their therapeutic actions doesn’t include all the relevant domains. (Negative symptoms such as low drive/motivation and impaired emotional processing and cognition impairments represent leading unmet therapeutic needs.)

Meanwhile, at a sub-clinical level, investigators have assessed features associated with schizophrenia and bipolar disorders that more closely align with underlying brain dysfunction. The National Institutes of Mental Health (NIMH) recently sponsored the Bipolar Schizophrenia Network on Intermediate Phenotypes to assess cognitive, neuroimaging, electrophysiological, and psychological markers to clarify the nature of our current disorders and explore new approaches to their classification.

Furthermore, NIMH has introduced the Research Domain Criteria (RDoC) to orient clinical research towards behavioral constructs with known neural networks, hypothesizing that this will enhance discovery at the cellular, molecular, and genetic levels that can then be translated back to aspects of currently defined disorders. For example, behavioral constructs such as fear processing are thought to relate to anxiety; impairments in a social processes construct may relate to interpersonal pathologies. The five constructs developed so far include negative valence, positive valence, cognition, social processes, and arousal/regulatory. These systems are viewed on a continuum from normal to pathological. It is expected that currently defined disorders will have impairments related to one or more of the five selected behavioral constructs, and identified pathologies will cut across current diagnostic boundaries.

This shift should have substantial effects on scientific enquiry. The field may move from a large number of genes contributing small effects on a heterogeneous clinical syndrome to assessment methods that enable genetic interrogation in relation to specific behavioral constructs, phenotypes, symptom dimensions, or neural circuit function. Disrupted brain physiology may be related to specific pathways underlying equally specific components of psychopathology–enabling therapeutic discovery related to a specific symptom or behavioral cluster.

An informed mapping of human illness phenotypes onto pre-clinical animal models may increase validity of translational science. The how and why questions can be examined in rodent models of behavioral constructs, generating hypotheses relevant to specific clinical pathology rather than syndrome. The fundamental phenotypes of schizophrenia can be identified and the relationship with clinical symptoms explored.

Clinicians may one day be able to see a patient with schizophrenia, specify the particular symptoms in each case, understand a connection with basic behavioral constructs and underlying brain dysfunction, and select suitable therapeutics.

Featured Image Credit: By Lee Scott. CC0 via Unsplash.

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