Beyond antipsychotics: pharmacologically-augmented cognitive therapies (PACTs) for schizophrenia.

The neuropathology of schizophrenia is substantial in scope and complexity. In patients, structural abnormalities in about 20 brain regions span wide swaths of cortical and subcortical tissue, reflecting processes presumably well advanced at birth. Roughly half as many regions are abnormal in unaffected relatives (cf. Swerdlow, 2011). Within any region, laminar synaptic and cellular arrangements may be perturbed, replacing ‘intended' spatial and chemical connections with dysfunctional alternatives. The likelihood that medications will functionally untangle these chaotic and dispersed connections in schizophrenia seems increasingly far-fetched. Cognitive therapies, broadly including cognitive-behavioral and neurorehabilitative therapies and cognitive training, may reduce symptoms and restore function in schizophrenia (McGurk et al, 2007; and Wykes et al, 2008) by engaging healthy neural systems to learn adaptive cognitive and behavioral strategies. The biology underlying learning-based neuroplasticity has been elaborated at levels extending from molecules to systems, and studies are now identifying neural changes accompanying clinical benefits of these specialized ‘learning therapies.' Conceivably, these neural changes and their corresponding therapeutic impact might be augmented via medications. Although controlling psychosis benefits ongoing cognitive interventions, drugs with pro-cognitive effects (rather than antipsychotics per se) might more specifically, and perhaps synergistically, enhance the clinical benefits of CTs. Drugs that enhance specific components of neurocognition, eg, working memory (WM), might be predicted to yield clinical benefits in schizophrenia only if paired with interventions that access those components, ie, utilize/place demands on enhanced WM. Similar reasoning underlies the use of anabolic steroids to promote exercise-increased muscle mass, or perhaps more importantly, the use of pro-extinction drugs to enhance therapeutic benefits of cognitive therapies for anxiety disorders (Ressler et al, 2004). Conversely, specific pro-cognitive drugs might be effective in augmenting the clinical benefits of cognitive therapies in schizophrenia even if (as existing data may suggest) they are ineffective when administered without the demands of cognitive therapies. Initial attempts to develop pharmacologically-augmented cognitive therapies (PACTs) are in progress, using drugs designed to overcome neuropathological changes in schizophrenia (eg, d-cycloserine (Gottlieb et al, 2011)); I have suggested that an alternative strategy might be to utilize medications that enhance spared neural functions in these patients (Swerdlow, 2011). Evidence for the requisite ‘spared' healthy neural circuitry in any given patient, and hence a target for PACTs, might be provided by specific neurophysiological changes in response to a single drug challenge. The use of a ‘test dose' to predict clinical benefit has been successful with interventions ranging from hormones to anti-Parkinsonian therapies to bronchodilators. The goal of enhancing ‘spared' function departs from the prevailing failed strategy of trying to use drugs to ‘undo' a lifetime of schizophrenia-related neuropathology. Based on the genetic and neurobiological heterogeneity of schizophrenia, biomarkers might identify subgroups of patients most sensitive to specific PACTs; in some cases, these biomarkers might include neurophysiological measures that identify spared neural circuits in these patients (Javitt et al, 2008). Importantly, the use of PACTs shifts our scientific focus from characterizing the widespread (and I submit, uncorrectable) neuropathology and its molecular antecedents in schizophrenia, to identifying areas of neurobiological resilience and function. In this strategy, our patients' spared neural resources become the next generation of therapeutic targets for drug development.