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ICOSR 2013óCan Drugs Boost Cognitive Therapies for Schizophrenia?

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 DíSouza 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 (DíSouza 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). DíSouza 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.óSavita Bhakta.

Comments on Related News


Related News: Boosting NMDA Receptors Improves Symptoms, Cognition in Schizophrenia

Comment by:  Hugo Geerts
Submitted 20 October 2013
Posted 20 October 2013
  I recommend the Primary Papers

The group around Dr. Hsien-Yuan Lane has published a number of papers on clinical trials in schizophrenia patients with agents that act on co-agonist sites of the NMDA-receptor. This time they report on the beneficial effects of augmentation therapy with high-dose benzoate, a D-amino acid oxidase inhibitor, on a number of clinical scales (about 25 subjects/treatment arm). The effect is substantial (effect sizes between 1.16 on the PANSS negative and 1.69 on the PANSS positive subscale). For instance, this effect size is about twice the value seen in clinical trials with bitopertin, a glycine transporter-1 inhibitor in a larger Phase II study (Umbricht et al., 2010). Only one dose of benzoate has been tested, so the issue of a possible inverse U-shape response that has been observed earlier for a similar target and supported by theoretical-mechanistic insights has not been addressed in this study. They took great care in balancing the treatment arms with regard to the type of basal antipsychotic medication and found that haldol and risperidone were particularly receptive for benzoate augmentation therapy.

Of interest is the observation that benzoate is a food additive (E210-E213) with an impressive record of safety, opening up the possibility of an easier treatment approach of lower levels of the drug be achieved using food strategies. It might therefore be of interest to test lower levels of benzoate as well.

Antipsychotics are often considered deleterious or neutral at best for cognitive improvement, so this augmentation study suggests that benzoate is able to reverse this trend of worsening. In addition, there were no correlations between changes in PANSS positive or EPS changes and changes in both PANSS negative or cognitive outcome. This suggests that the observed effect of the compound is unlikely to be indirectly due to an improvement in PANSS positive symptoms or motor side effects, suggesting a genuine impact on the negative or cognitive subscales.

With regard to cognition, from the MATRICS subscale, the authors only found speed of processing and visual learning and memory to be significantly improved with the active treatment. However, this is one of the few trials in which the global composite score increased more with treatment than the placebo, despite the possible practice effect. Nevertheless, it underscores the difficulty of improving all seven domains of the cognitive MATRICS scale.

With the caveat of low numbers in the treatment arm, this study has to be recommended because it once again suggests a path forward for glutamatergic strategies. The glutamatergic system is currently the focus of much research in psychiatric indications (such as ketamine in depression). However the major problem, unlike older dopaminergic and neuromodulatory strategies, is finding a balance between excitation and inhibition in the human brain, and the feedback mechanism that operates, that makes it sometimes difficult to find the best dose-range for any treatment paradigm. The authors of this paper, however, show that this is possible.

References:

Umbricht D, Yoo K, Youssef E, Dorflinger E, Martin-Facklam M, Bausch A, Arrowsmith R, Alberati D, Marder S, Santarelli L. Glycine Transporter Type 1 (GLYT1) Inhibitor RG1678: Positive Results of the Proof-of-Concept Study for the Treatment of Negative Symptoms in Schizophrenia. Neuropsychopharmacology. 2010; 35:S320-321.

View all comments by Hugo Geerts

Related News: Boosting NMDA Receptors Improves Symptoms, Cognition in Schizophrenia

Comment by:  Michael McFarland
Submitted 5 November 2013
Posted 11 November 2013

Sodium benzoate combined with ascorbic acid produces benzene, a known carcinogen. I hope that another D-amino acid oxidase inhibitor can be found easily.

View all comments by Michael McFarland