The findings discussed in this Review suggest that impaired working memory and auditory information processing in schizophrenia are attributable, at least in part, to a complex set of alterations in cortical circuitry in the DLPFC and AI, respectively. However, the emergence of working memory and prosody depends upon more distributed cortical networks, and thus alterations within local circuits must be considered within the broader organization of the cortex and its connections with subcortical structures. Although the frequency of alterations in specific components of these cortical circuits are common enough to be consistently detected in different cohorts of subjects identified by a common set of diagnostic criteria, the extent to which these alterations are restricted to only certain types of individuals with schizophrenia remains to be determined; this knowledge is essential for considering the opportunities for personalized medicine in the treatment of schizophrenia.
Rational pharmacological treatments for schizophrenia are designed to normalize the pathophysiology that mediates the clinical feature of interest (Figure ). Thus, any molecule identified as a drug target must be understood in the context of the pathological circuit, and ideally the effects of compounds with the desired activity at that target are evaluated using both direct assessments of pathophysiology (e.g., EEG, functional MRI, and PET) and sensitive and specific measures of the clinical feature, as well as broader and more standard measures of neuropsychological function and symptomatology. Indeed, recent studies suggest that broad measures employing neuropsychological test batteries, although advantageous for clinical trials because of their psychometric properties (e.g., test-retest reliability), are prone to practice effects that might obscure the therapeutic effects of novel drugs (122
Any given pathological entity in a disease process could represent a cause (an upstream factor related to the disease pathogenesis), a consequence (a deleterious effect of a cause), or a compensation (a response to either cause or consequence that helps restore homeostasis) (73
). Although understanding these distinctions is clearly necessary for drug design, as it determines the required mode of action of the drug, making these distinctions requires an understanding of the functional properties of the cortical circuitry in which they are embedded. For example, the idea that GABAA
receptors containing α2
subunits are upregulated in pyramidal neurons due to a deficit in GABA input from chandelier neurons led to the use of a novel positive allosteric modulator of this receptor subtype that improved both working memory function and prefrontal γ-band oscillations in a small randomized controlled trial of subjects with schizophrenia (98
). Similarly, the idea that DA D1 receptors are upregulated to compensate for a deficient DA innervation of the DLPFC has motivated attempts to develop selective approaches for modulating activity at cortical DA D1 receptors (77
). In this regard, PET-based assessments of the degree of DA D1 receptor upregulation in individual patients may help in guiding therapy to maximize the likelihood of obtaining optimal levels of DA D1 receptor stimulation.
Finally, analyses of pathological circuits might lead to the future identification and validation of new types of therapeutic targets beyond the manipulation of neurotransmitter systems. For example, spine-specific kinases, whose activity regulates spine size, number, and function, might be of potential value as novel targets (48
). If the adolescence-related pruning of dendritic spines is, as discussed above, critical in the emergence of the clinical features of schizophrenia, then such compounds might provide a means for secondary prevention through early intervention in high-risk individuals.