Biotypes in Psychosis: Has the RDoC Era Arrived?

Schizophrenia remains one of the most common and debilitating of all psychiatric disorders. This syndromewasfirst described by Kraepelin as “dementia praecox” in the late 1800s and then refined as “schizophrenia” by Bleuler in the early 1900s. The current focus on positive symptoms emerged after the introduction of antipsychotic agents in the 1950s and has remained little changed over the past 30 years. Nevertheless, clinicians are well aware of the clinical heterogeneity of psychotic disorders, famously captured by Bleuler’s term “the group of the schizophrenias.” Psychiatry has yet to resolve these into component disorders. The recently initiated Research Domain Criteria (RDoC) initiative proposes use of neurobiological measures for development of a neuroscience-based nosology of mental disorders (1). The present issue of the Journal contains three articles that address the issue using complementary biomarker approaches. Allen et al. (2) highlight the utility of MRI perfusion measures for detecting pathology early in the course of schizophrenia. As opposed to blood-oxygen-level-dependent (BOLD) imaging, perfusion measures such as arterial spin labeling detect absolute, rather than relative, blood flow in the brain and thus can detect basal hyperperfusion across individuals. Prior perfusion MRI techniques required the use of tracer agents such as gadolinium for blood volume quantification. Nevertheless, the findings from the study by Allen et al. closely echo findings from prior perfusion imaging studies in at-risk subjects (3), as well as results of neurochemical imaging using magnetic resonance spectroscopy (4). In those studies, hippocampalhypermetabolismpredicted not only symptoms but also hippocampal atrophy over time (3). Similar predictive results were observed for glutamatergic hyperactivity (4). In rodents, administration of theN-methylD-aspartate receptor (NMDAR) antagonist ketamine produces a patternof glutamatergic hyperactivitywithincortico-limbicthalamic circuits that resembles the pattern observed in schizophrenia (3). As in the study byAllen et al. (2), the hyperperfusion persists despite antipsychotic treatment, but it is reversed by using glutamatergic agents such as the mGluR2/3 agonist pomaglumetad (3) or theNMDARglycine-site agonist D-serine (5). Similarly, in at-risk individuals, treatment with D-serine leads to reductions both in symptoms and in serum levels of interleukin-6, which may be an important mediator of the NMDAR antagonist effect (6). The work of Allen et al. (2) and other recent studies of atrisk individuals show that symptoms, inflammatory changes, and hippocampal hyperperfusion are time-limited in the majority of subjects even without specific treatment, with only 10% of individuals converting to schizophrenia. However, the symptoms and associated neurophysiological deficits may significantly undermine ongoing function (e.g., 7). As do other investigators, therefore,Allenetal. argue forearlier intervention with disease-modifying, rather than symptom-modifying, approaches (8). The study by Greenwood et al. (9) reported in this issue targeted sensory gating deficits, using the measures of prepulse inhibition (PPI) and P50 gating. These are observable traits that are linked both to the personal experience of “flooding” that may occur early in the course of schizophrenia and to the underlying pathophysiology (10). Like hippocampal hyperperfusion, therefore, sensory gatingmay be amenable to implementation as a clinical biomarker to identify etiological subgroups, particularly those responsive to a7-based cholinergic intervention. Moreover, both hippocampal hyperperfusion and impaired sensory gatingmay bemanifestations of the same local circuit dysfunction within brainstem reticular pathways (10). Greenwood et al. (9) found that the heritability of PPI and P50gating is significantly higher in familial, relative to sporadic, cases of schizophrenia. Analogous to Tolstoy’s observation regarding happiness, all normal P50s may therefore be alike, but each at-risk family may harbor its own, distinct P50 abnormality. In addition, Greenwood et al. highlight the greater negative symptoms, worse global function, and lower educational achievement in familial schizophrenia, making early detection within familial cases especially important. The third related study reported in this issue, byClementz et al. (11), applied neurobiological measures across psychotic disorders, rather than being restricted to DSM-based schizophrenia. The present diagnostic distinction between schizophrenia and bipolar disorder comes from Kraepelin’s classic descriptions of “dementia praecox” and “manic depressive insanity” as separate illnesses. However, as recently discussed (12), even Kraepelin in later years became concerned about the twoversus one-psychosis concept. Furthermore, recent genetic findings show substantial overlap across disorders (12). The approach taken by Clementz et al. is thus consistent not only with RDoC concepts, but also with the increasing Clinicians are well aware of the clinical heterogeneity of psychotic disorders, famously captured by Bleuler’s term “the group of the schizophrenias.”