Because d-serine is a low-potency NMDAR agonist, its specific clinical utility is likely limited. Nevertheless, the present findings suggest first that NMDAR agonists as a class may be useful in potentiating plasticity during auditory remediation training and, second, that the auditory plasticity paradigm may be useful in evaluating potential novel treatment approaches. In addition, while the large majority of NMDAR agonist studies in schizophrenia have utilized continuous treatment with NMDAR agonists for therapeutic intervention, the present study supports episodic (once weekly) intervention for cognition enhancement. Moreover, plasticity-based remediation targeting auditory deficits is reported to improve not only auditory-level function, but also higher-level processes such as verbal working memory and global cognitive function (Fisher et al. , 2009; Vinogradov et al. , 2012). In previous studies, alterations in neurophysiological responses were observed following ∼30–50 h of training (Popov et al. , 2012; Dale et al. , 2016). A noteworthy result of the present study is that we observed neurophysiological improvement following only two sessions paired with an NMDAR agonist. Because of the different interventions, the comparability between the sets of findings is uncertain, and future studies are required to determine whether similar effects will be observed in combination with the types of targeted exercises that have been used previously for long-term auditory remediation.
Finally, an interesting result from the present study is that the magnitude of effect was significantly larger in patients with schizophrenia who received two consecutive days of d-serine than it was in those who only received an initial administration. Similar paradoxical effects have also been noted in rodent investigations, suggesting that greatest effects are on consolidation rather than initiation of long-term potentiation (Quartermain et al. , 1994; Santini et al. , 2001; Liu et al. , 2014). The time course of the present effects may be best explained by an emerging literature suggesting that long-term potentiation occurs in two different phases—an initial NMDAR-induced increase in AMPA receptor trafficking that occurs over minutes, followed by a delayed increase in NMDAR trafficking that occurs over hours (consolidation) (Watt et al. , 2004).
An increase in NMDAR trafficking would also potentially account for the ‘priming’ effect observed in the present study whereby both physiological and behavioural effects were much larger following two consecutive treatments of d-serine than following a single day. Our results are also consistent with d-cycloserine studies suggesting efficacy only when an NMDAR agonist is given on the first session (Gottlieb et al. , 2011), and overall suggest the need for further investigations into the most effective timing of NMDAR-based intervention relative to plasticity-based treatment.