Abstract
The combination of pharmacotherapy and cognitive retraining (CRT) for the cognitive deficits of schizophrenia may be more efficacious than either approach alone, but this has not yet been tested. This study evaluated the feasibility, safety, tolerability, and efficacy of 12 weeks of D-serine, combined with CRT in the treatment of cognitive deficits in schizophrenia at two academic sites in parallel, in India and the United States. In a randomized, partial double-blind, placebo-controlled, parallel-group design, 104 schizophrenia subjects (US site=22, Indian site=82) were randomized to: (1) D-serine (30 mg/kg)+CRT (5 h/week), (2) D-serine+control CRT, (3) CRT+placebo D-serine, and (4) placebo+control CRT. Completion rates were 84 and 100% in the Indian and US samples, respectively. On various outcome measures of safety and tolerability, the interventions were well tolerated. D-Serine and CRT did not show any significant effect on the Global Cognitive Index, although both interventions showed differential site effects on individual test performance. CRT resulted in a significant improvement in Verbal Working Memory, and a trend toward improvement in Attention/Vigilance. This is the first study to demonstrating the feasibility, safety, and tolerability of combination pharmacotherapy and CRT in a multicenter international clinical trial. These preliminary findings provide support for future studies using higher doses of D-serine that have been shown to be efficacious or other pharmacotherapies, along with the newer cognitive remediation strategies that are individualized and that target basic information processing.
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References
Addington D, Addington J, Schissel B (1990). A depression rating scale for schizophrenics. Schizophr Res 3: 247–251.
Arnsten AF, Cai JX, Murphy BL, Goldman-Rakic PS (1994). Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys. Psychopharmacology (Berl) 116: 143–151.
Barnes TR (1989). A rating scale for drug-induced akathisia. Br J Psychiatry 154: 672–676.
Bell MD, Fiszdon JM, Bryson G (2009). Attention training in schizophrenia: differing responses to similar tasks. J Psychiatr Res 43: 490–496.
Bradley SR, Lameh J, Ohrmund L, Son T, Bajpai A, Nguyen D et al (2010). AC-260584, an orally bioavailable M(1) muscarinic receptor allosteric agonist, improves cognitive performance in an animal model. Neuropharmacology 58: 365–373.
Buchanan RW, Freedm, an R, Javitt DC, Abi-Dargham A, Lieberman JA (2007). Recent advances in the development of novel pharmacological agents for the treatment of cognitive impairments in schizophrenia. Schizophr Bull 33: 1120–1130.
Chen SH, Thomas JD, Glueckauf RL, Bracy OL (1997). The effectiveness of computer-assisted cognitive rehabilitation for persons with traumatic brain injury. Brain Inj 11: 197–209.
Coyle JT, Tsai G (2004). The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology (Berl) 174: 32–38.
d'Amato T, Bation R, Cochet A, Jalenques I, Galland F, Giraud-Baro E et al (2011). A randomized, controlled trial of computer-assisted cognitive remediation for schizophrenia. Schizophr Research 125: 284–290.
D'Souza DC, Singh N, Elander J, Carbuto M, Pittman B, de Haes JU et al (2012). Glycine transporter inhibitor attenuates the psychotomimetic effects of ketamine in healthy males: preliminary evidence. Neuropsychopharmacology 37: 1036–46.
Giustizieri M, Armogida M, Berretta N, Federici M, Piccirilli S, Mercuri NB et al (2008). Differential effect of carbamazepine and oxcarbazepine on excitatory synaptic transmission in rat hippocampus. Synapse 62: 783–789.
Gordon M (1986). Microprocessor-based assessment of attention deficit disorders (ADD). Psychopharmacol Bull 22: 288–290.
Green MF, Kern RS, Braff DL, Mintz J (2000). Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the “right stuff”? Schizophr Bull 26: 119–136.
Gustafson EC, Stevens ER, Wolosker H, Miller RF (2007). Endogenous D-serine contributes to NMDA-receptor-mediated light-evoked responses in the vertebrate retina. J Neurophysiol 98: 122–130.
Guy W (1976). (reprinted 1991)) ECDEU Assessment Manual for Psychopharmacology. U.S. Department of Health, Educaiton and Welfare: Washington DC.
Heinrichs DW, Hanlon TE, Carpenter WT (1984). The Quality of Life Scale: an instrument for rating the schizophrenic deficit syndrome. Schizophr Bull 10: 388–398.
Heinrichs RW, Zakzanis KK (1998). Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 12: 426–445.
Hodge MA, Siciliano D, Withey P, Moss B, Moore G, Judd G et al (2010). A randomized controlled trial of cognitive remediation in schizophrenia. Schizophr Bulletin 36: 419–427.
Homayoun H, Moghaddam B (2010). Group 5 metabotropic glutamate receptors: role in modulating cortical activity and relevance to cognition. Eur J Pharmacol 639: 33–39.
Javitt DC (2007). Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. Int Rev Neurobiol 78: 69–108.
Javitt DC (2009). Glycine transport inhibitors for the treatment of schizophrenia: symptom and disease modification. Curr Opin Drug Discov Devel 12: 468–478.
Javitt DC, Duncan L, Balla A, Sershen H (2005). Inhibition of system A-mediated glycine transport in cortical synaptosomes by therapeutic concentrations of clozapine: implications for mechanisms of action. Mol Psychiatry 10: 275–287.
Kantrowitz JT, Malhotra AK, Cornblatt B, Silipo G, Balla A, Suckow RF et al (2010). High dose D-serine in the treatment of schizophrenia. Schizophr Res 121: 125–130.
Kapur S, Mamo D (2003). Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 27: 1081–1090.
Kay SR, Opler LA, Lindenmayer JP (1989). The Positive and Negative Syndrome Scale (PANSS): rationale and standardisation. Br J Psychiatry Suppl 7: 59–67.
Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM et al (2007). Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 64: 633–647.
Keefe RS, Eesley CE, Poe MP (2005). Defining a cognitive function decrement in schizophrenia. Biol Psychiatry 57: 688–691.
Keefe RS, Malhotra AK, Meltzer HY, Kane JM, Buchanan RW, Murthy A et al (2008). Efficacy and safety of donepezil in patients with schizophrenia or schizoaffective disorder: significant placebo/practice effects in a 12-week, randomized, double-blind, placebo-controlled trial. Neuropsychopharmacology 33: 1217–1228.
Keefe RS, Vinogradov S, Medalia A, Silverstein SM, Bell MD, Dickinson D et al (2011). Report from the working group conference on multisite trial design for cognitive remediation in schizophrenia. Schizophr Bull 37: 1057–1065.
Klingberg S, Wolwer W, Engel C, Wittorf A, Herrlich J, Meisner C et al (2011). Negative symptoms of schizophrenia as primary target of cognitive behavioral therapy: results of the randomized clinical TONES study. Schizophr Bull 37 (Suppl 2): S98–110.
Krystal JH, D'Souza DC, Mathalon D, Perry E, Belger A, Hoffman R (2003). NMDA receptor antagonist effects, cortical glutamatergic function, and schizophrenia: toward a paradigm shift in medication development. Psychopharmacology (Berl) 169: 215–233.
Kurtz MM, Seltzer JC, Fujimoto M, Shagan DS, Wexler BE (2009). Predictors of change in life skills in schizophrenia after cognitive remediation. Schizophr Res. 107: 267–274.
Lee CY, Fu WM, Chen CC, Su MJ, Liou HH (2008). Lamotrigine inhibits postsynaptic AMPA receptor and glutamate release in the dentate gyrus. Epilepsia 49: 888–897.
Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K (1987). The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl 334: 1–100.
McGurk SR, Mueser KT, Feldman K, Wolfe R, Pascaris A (2007a). Cognitive training for supported employment: 2-3 year outcomes of a randomized controlled trial. Am J Psychiatry 164: 437–441.
McGurk SR, Twamley EW, Sitzer DI, McHugo GJ, Mueser KT (2007b). A meta-analysis of cognitive remediation in schizophrenia. Am J Psychiatry 164: 1791–1802.
Ninan I, Jardemark KE, Wang RY (2003). Differential effects of atypical and typical antipsychotic drugs on N-methyl-D-aspartate- and electrically evoked responses in the pyramidal cells of the rat medial prefrontal cortex. Synapse 48: 66–79.
O'Donnell CJ, Rogers BN, Bronk BS, Bryce DK, Coe JW, Cook KK et al (2010). Discovery of 4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane (CP-810,123), a novel alpha 7 nicotinic acetylcholine receptor agonist for the treatment of cognitive disorders in schizophrenia: synthesis, SAR development, and in vivo efficacy in cognition models. J Med Chem 53: 1222–1237.
Patterson TL, Goldman S, McKibbin CL, Hughs T, Jeste DV (2001a). UCSD Performance-Based Skills Assessment: development of a new measure of everyday functioning for severely mentally ill adults. Schizophr Bull 27: 235–245.
Patterson TL, Lacro J, McKibbin CL, Moscona S, Hughs T, Jeste DV (2002). Medication management ability assessment: results from a performance-based measure in older outpatients with schizophrenia. J Clin Psychopharmacol 22: 11–19.
Patterson TL, Moscona S, McKibbin CL, Davidson K, Jeste DV (2001b). Social skills performance assessment among older patients with schizophrenia. Schizophr Res 48: 351–360.
Radek RJ, Kohlhaas KL, Rueter LE, Mohler EG (2010). Treating the cognitive deficits of schizophrenia with alpha4beta2 neuronal nicotinic receptor agonists. Curr Pharm Des 16: 309–322.
Rebola N, Srikumar BN, Mulle C (2010). Activity-dependent synaptic plasticity of NMDA receptors. J Physiol 588 (Pt 1): 93–99.
Silverstein SM, Spaulding WD, Menditto AA, Savitz A, Liberman RP, Berten S et al (2009). Attention shaping: a reward-based learning method to enhance skills training outcomes in schizophrenia. Schizophr Bull 35: 222–232.
Simpson GM, Angus JW (1970). A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 212: 11–19.
Tsang HW, Leung AY, Chung RC, Bell M, Cheung WM (2010). Review on vocational predictors: a systematic review of predictors of vocational outcomes among individuals with schizophrenia: an update since 1998. Aust N Z J Psychiatry 44: 495–504.
Umbricht D (2010). Glycine Transporter Type 1 (GLYT1) Inhibitor RG1678: Positive Results of the Proof-of-Concept Study for the Treatment of Negative Symptoms in Schizophrenia’. 49th Annual Meeting of the American College of Neuropsychopharmacology Miami Beach, Florida.
Wykes T (2010). Cognitive remediation therapy needs funding. Nature 468: 165–166.
Wykes T, Spaulding WD (2011). Thinking about the future cognitive remediation therapy--what works and could we do better? Schizophr Bull 37 (Suppl 2): S80–90.
Acknowledgements
This study was supported by funding from the Stanley Medical Research Institute (to Deepak C D’Souza), the Donaghue Foundation (to Deepak C D’Souza), a VA Career Award (to Edward Perry), the VA Schizophrenia Center, and the VA Cooperative Studies Program. We thank John H Krystal for his advice in conceptualizing the study.
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Deepak Cyril D’Souza currently receives research grant support administered through Yale University School of Medicine from Astra Zeneca, Abbott Laboratories, Eli Lilly Inc., Organon, Pfizer , and Sanofi, and is a consultant to Bristol Meyers Squibb. Danielle Abi-Saab is currently an employee of Roche Pharmaceuticals and owns stocks with Roche. Her spouse is an employee of Shire and they also own stocks in Shire, Abbott Labs, and Novartis. Chittaranjan Andrade: has received support to conduct clinical trials from Phyto-Pharma, Gufic Ltd, Zandu Pharmaceuticals, Aristo Pharmaceuticals, Cybele Laboratories, Himalaya Drug Company, Natural Remedies, Arya Vaidya Nilayam, Lupin Laboratories, Corcept, Natreon, and Glaxo SmithKline. He has also received lecture fees from Pfizer (payment made directly to a registered charity). He publishes an e-newsletter, which is supported by Sun Pharmaceuticals (payments are made directly to registered charities). He has provided paid consultancy to Astra Zeneca, Wyeth, Sun Pharma, Intas Pharma, and Torrent Pharma (payments either in the form of textbooks or other academic materials or directed to charities). He is also principal investigator and medical monitor for a multicenter, investigator-initiated investigation of the efficacy of Sensoril, funded by Natreon. He authors and receives authorship payments for Critical Readings in Psychiatry series (current publisher, Zydus Neurosciences). The other authors declare no conflict of interest.
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D'Souza, D., Radhakrishnan, R., Perry, E. et al. Feasibility, Safety, and Efficacy of the Combination of D-Serine and Computerized Cognitive Retraining in Schizophrenia: An International Collaborative Pilot Study. Neuropsychopharmacol 38, 492–503 (2013). https://doi.org/10.1038/npp.2012.208
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DOI: https://doi.org/10.1038/npp.2012.208
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