As part of our ongoing coverage of the 2013 International Congress on Schizophrenia Research (ICOSR), held 21-25 April in Orlando, Florida, we bring you session summaries from some of the Young Investigator Travel Award winners. For this report, we thank Savita Bhakta of the University of California, San Diego.
17 June 2013. Neurocognitive deficits are a core feature of schizophrenia and are known to predict functional outcome in patients with this illness (Weinberger et al., 1986; Barch, 2005; Keedy et al., 2006; Keefe et al., 2006). However, medications currently available to treat schizophrenia diminish positive symptoms and, to a lesser extent, negative symptoms, but have little or no beneficial effect on neurocognitive symptoms. Currently available cognitive enhancing strategies, both pharmacological and non-pharmacological, produce only small to modest effect size improvements in function and cognition in schizophrenia. Because of this, strategies are being explored for pharmacologic augmentation of cognitive therapies (dubbed "PACT") (Swerdlow, 2011; 2012). Specifically, PACT strategies pair drugs that target particular cognitive domains (e.g., attention/vigilance) with cognitive therapies that access/put demands on those domains. A proof of concept for this approach is being developed and applied through the use of drugs that selectively enhance the therapeutic benefits of cognitive and behavioral interventions for anxiety disorders (Ressler et al., 2004).
The ICOSR Monday morning symposium, "Pharmacological Approaches for Facilitating Non-pharmacological Treatments," chaired by Steve Marder of the University of California, Los Angeles, and Sophia Vinogradov of the University of California, San Francisco, covered results from pilot studies using such PACT approaches to treat cognitive deficits in schizophrenia.
The first speaker, Donald Goff of the New York University School of Medicine discussed the combined use of D-cycloserine and cognitive remediation therapy in schizophrenia patients. D-cycloserine is a partial agonist at the NMDA receptor and is known to enhance neuroplasticity. Researchers have widely studied the drug to treat anxiety disorders by combining it with fear conditioning and extinction (Kalisch et al., 2009). The medication is found to enhance 24-hour recall on a procedural memory task dependent on sleep-associated improvement and to rescue an extinction deficit on a conditioned taste aversion memory task in BDNF Met/Met mice (Yu et al., 2009). D-cycloserine facilitates cognitive behavior therapy (CBT) for delusions in schizophrenia patients (Gottlieb et al., 2011) and delayed thematic recall in schizophrenia. In an ongoing randomized, double-blind, placebo-controlled study with once-a-week dosing of D-cycloserine (placebo vs. active 50 mg po) combined with three to five times weekly Posit Science sessions for eight weeks, patients receiving D-cycloserine + Posit Science showed significant improvement on an auditory discrimination task compared to D-cycloserine alone or the placebo + Posit Science group; however, there was no change in cognitive performance.
The second speaker, Cyril D’Souza of Yale University, New Haven, Connecticut, presented data from a multisite study investigating the feasibility, safety, and efficacy of D-serine and cognitive remediation therapy (CRT) in schizophrenia patients (D’Souza et al., 2013). This randomized, double-blind, placebo-controlled study combined D-serine (placebo vs. active 30 mg/kg orally) given daily, along with computer-based CRT using CogRehab software versus control video shows five hours a week for 12 weeks and follow-up at four, 12, and 24 weeks after completion of study. One hundred four schizophrenia patients completed the study at two sites in the U.S. and India. The results revealed that it was feasible to conduct such studies; there were no adverse side effects reported, and D-serine at the dose of 30 mg/kg was well tolerated. However, there were no differences in cognitive performance among the four groups (D-serine alone, D-serine + CRT, CRT alone and placebo, and D-serine + control video shows). D’Souza noted the limitations of study as 1) having low power in each group to conduct meaningful comparison; 2) low dose of D-serine (recently approved dose is 60 mg/kg); and 3) limitation of the CogRehab CRT.
Larry Seiver of Mount Sinai Medical School in New York City was the next speaker, and he presented findings from an ongoing study combining guanfacine with CRT in schizotypal personality disorder (SPD) patients. He discussed the uniqueness of the SPD patient population and its resemblance to the schizophrenia patient population in terms of neurocognitive deficits. Findings from a completed study with guanfacine in SPD patients showed guanfacine to improve performance on a working memory task (McClure et al., 2007). He described an ongoing study of a dopamine receptor 1 agonist, DAR-0100, in schizophrenia patients, and mentioned that early findings found DAR-0100 to have positive effects on cognition. He also described an ongoing pilot study examining the combined effects of guanfacine and CRT (computerized tasks in a group setting twice weekly) for eight weeks in a double-blind, randomized, controlled trial comparing CRT alone with guanfacine alone or guanfacine + CRT. He was interested in identifying genes that were associated with positive outcome and identifying any predictive variables of procognitive response.
Session co-chair Steve Marder was the last speaker, and he discussed an ongoing study combining oxytocin with social cognitive training (SCT) to improve social cognition in schizophrenia patients. Social cognition is related to community function (Horan et al., 2011) and can be classified into low and high levels. Low-level social cognition involves recognizing facial expressions, whereas the high level involves identifying sarcasm. Studies have shown that both emotional and social training improve low-level facial affect perception. Oxytocin, a neuropeptide, has been extensively studied to improve multiple aspects of social behavior such as increasing trust (Kosfeld et al., 2005), increasing empathic accuracy in healthy men (Bartz et al., 2010), and reducing psychotic symptoms (Bartz et al., 2011). Marder described two studies: one evaluating the effectiveness of oxytocin alone and the other combining oxytocin with SCT.
Marder and his colleagues found that a single dose of oxytocin (placebo vs. active 40 IU intranasally) in a crossover, randomized pilot study improved performance on social cognitive measures. He also reported preliminary findings from the ongoing study combining oxytocin with SCT, in which both the placebo and oxytocin groups improved on social cognitive composite scores. SCT alone was found to be effective for improving low-level social cognitive measures, and oxytocin appeared to facilitate learning of higher-level social cognitive abilities, particularly empathic accuracy in schizophrenia patients.
Finally, Sophia Vinogradov summed up the symposium and highlighted the shift in cognitive research toward combining pharmacological and behavioral approaches to improve cognitive outcomes in schizophrenia. She also pointed out the complexity in designing such studies and emphasized focus on the specific cognitive domain using an experimental medicine approach to understand the neurobiology of the cognitive deficits and cognitive therapies, and to identify predictors for procognitive response.—Savita Bhakta.