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. Author manuscript; available in PMC: 2022 Dec 21.
Published in final edited form as: Schizophr Res. 2018 Apr 24;207:63–69. doi: 10.1016/j.schres.2018.04.011

Association between increased serum D-serine and cognitive gains induced by intensive cognitive training in schizophrenia

Rogerio Panizzutti a,b,c, Melissa Fisher d, Coleman Garrett c, Wai Hong Man c, Walter Sena b, Caroline Madeira b, Sophia Vinogradov d
PMCID: PMC9770102  NIHMSID: NIHMS1851704  PMID: 29699895

Abstract

Neuroscience-guided cognitive training induces significant improvement in cognition in schizophrenia subjects, but the biological mechanisms associated with these changes are unknown. In animals, intensive cognitive activity induces increased brain levels of the NMDA-receptor co-agonist D-serine, a molecular system that plays a role in learning-induced neuroplasticity and that may be hypoactive in schizophrenia. Here, we investigated whether training-induced gains in cognition were associated with increases in serum D-serine in outpatients with schizophrenia. Ninety patients with schizophrenia and 53 healthy controls were assessed on baseline serum D-serine, L-serine, and glycine. Schizophrenia subjects performed neurocognitive tests and were assigned to 50 hours of either cognitive training of auditory processing systems (N=47) or a computer games control condition (N=43), followed by reassessment of cognition and serum amino acids. At study entry, the mean serum D-serine level was significantly lower in schizophrenia subjects vs. healthy subjects, while the glycine levels were significantly higher. There were no significant changes in these measures at a group level after the intervention. However, in the active training group, increased D-serine was significantly and positively correlated with improvements in global cognition and in verbal learning and memory. No such associations were observed in the computer games control subjects, and no such associations were found for glycine. D-serine may be involved in the neurophysiologic changes induced by cognitive training in schizophrenia. Pharmacologic strategies that target D-serine co-agonism of NMDA-receptor functioning may provide a mechanism for enhancing the behavioral effects of intensive cognitive training.

Keywords: neuroplasticity, NMDA receptors, cognitive remediation, schizophrenia

1. Introduction

Schizophrenia is characterized by a range of neurocognitive deficits, including impairments in verbal learning and memory. We have performed a series of studies investigating the effects of targeted cognitive training of auditory processing and verbal learning to enhance verbal memory function in schizophrenia, based on principles of learning-induced neuroplasticity (Fisher et al., 2009). This program of intensive cognitive training (e.g., 50 hours over 10 weeks) focuses on the accuracy, the temporal resolution and the power of auditory inputs feeding working and explicit memory processes. In studies of both persistently ill participants (average age of 40 years) and in recent-onset subjects (average age of 21 years), we have found significant improvements in verbal learning and memory and in general cognition, when compared to a computer games control condition (Fisher et al., 2009; Fisher et al., 2015; Fisher et al., 2016). Cognitive gains persisted 6 months after cessation of training (Fisher et al., 2010); showed an inverse association with anticholinergic burden (Vinogradov et al., 2009b); and were associated with variations in the catechol-O-methyltransferase (COMT) gene (Panizzutti et al., 2013). Subjects who were in the active training group also demonstrated a significant increase in serum brain-derived neurotrophic factor (BDNF) levels (Vinogradov et al., 2009a). Despite these promising results, many open questions remain about the neurophysiologic mechanisms harnessed during successful training.

It is now well-established that activation of NMDA receptors is necessary for experience-dependent neuroplasticity (Clem et al., 2008), likely through their role in long-term potentiation, a key cellular mechanism involved in learning and memory (Whitlock et al., 2006). Long-term potentiation is modulated by D-serine, an endogenous co-agonist of NMDA receptors (Panatier et al., 2006). Impaired NMDA receptor activity is believed to be involved in the pathophysiology of schizophrenia (Coyle, 2006), and several lines of evidence suggest that decreased availability of D-serine contributes to this hypofunction of NMDA receptors. For example, D-serine levels have been found to be decreased in the blood (Calcia et al., 2012; Hashimoto et al., 2003; Yamada et al., 2005; Yamamori et al., 2014) and in the cerebrospinal fluid (Bendikov et al., 2007; Hashimoto et al., 2005) of schizophrenia patients, although conflicting results for blood levels have also been reported (Hons et al., 2008; Ohnuma et al., 2008; Ozeki et al., 2016). Also in corroboration to the hypofunction evidences, genetic studies show an association between schizophrenia and the G72 gene, whose product appears to interact with the D-serine degrading enzyme D-amino acid oxidase (Chumakov et al., 2002; Detera-Wadleigh and McMahon, 2006). Postmortem studies demonstrate increased activity of D-amino acid oxidase in schizophrenia patients (Burnet et al.; Madeira et al., 2008), while clinical trials with D-serine yield improved positive, negative and cognitive symptoms (Heresco-Levy et al., 2005; Kantrowitz et al., 2010; Tsai et al., 1998).

The brain is the sole significant source of endogenous D-serine, which is synthesized from the racemization of L-serine catalyzed by serine racemase (De Miranda et al., 2000; Wolosker et al., 1999). D-serine crosses the blood-brain barrier bi-directionally and is detectable in serum; serum levels correlate with brain levels in animal studies (Bauer et al., 2005; Hashimoto, 2002; Hashimoto and Chiba, 2004). Although D-serine has been proposed as a serum biomarker for schizophrenia, its levels are not static; a study showed that serum D-serine was significantly increased in schizophrenia patients from the time of admission to the time of discharge as their clinical symptoms improved (Ohnuma et al., 2008). Such changes in serum D-serine may possibly be due to increased NMDA receptor activity; indeed, activation of both NMDA and non-NMDA glutamate receptors has been shown to increase extracellular D-serine levels (Kartvelishvily et al., 2006; Kim et al., 2005; Mustafa et al., 2009; Ribeiro et al., 2002; Schell et al., 1995).

Given the putative role of D-serine in schizophrenia, as well as the established role of NMDA receptors and of D-serine in neuroplasticity and experience-dependent learning, we asked whether serum D-serine levels in schizophrenia participants could be affected by a course of intensive cognitive training. To investigate this hypothesis, we posed two questions retrospectively: 1) Could we replicate earlier findings of reduced serum D-serine levels in schizophrenia outpatients who participated in our cognitive training studies? 2) Were the cognitive gains in the schizophrenia subjects who underwent intensive “neuroplasticity-informed” auditory system training associated with changes in serum D-serine levels?

To answer these questions, we measured levels of the free amino acids D-serine and L-serine from serum samples obtained at baseline (study entry), and after 40-50 hours (8-10 weeks) of either auditory processing and auditory working memory training exercises or commercial computer games, in 90 schizophrenia subjects who participated in our studies and on whom we had serum samples.

2. Methods

2.1. Participants

Subjects were obtained from our completed randomized controlled trials (RCT) of neuroplasticity-informed computerized cognitive training in adults with persistent schizophrenia (Fisher et al., 2009; Vinogradov et al., 2009a; Vinogradov et al., 2009b), N= 74, and in young adults with recent-onset schizophrenia (who were within 5 years of illness onset), N= 57 ClinicalTrials.gov NCT00312962 and NCT00694889 respectively (Figure 1). Since the trial design and the assessment and cognitive training protocols were virtually identical between the two studies, serum data and neurocognitive data were pooled for the purposes of the present analysis. This resulted in a total sample of 90 clinically stable schizophrenia outpatients with a mean age of 36.72 (SD= 13.79). Fifty-three healthy comparison subjects were recruited from the community. Inclusion criteria were: Axis I diagnosis of schizophrenia or schizoaffective disorder (determined by the DSM-IV SCID) or, for healthy subjects, no Axis I or Axis II psychiatric disorder (SCID-NP); no substance dependence or current substance abuse; good general physical health; English as first language. Table 1 presents subject demographics, baseline clinical status, and smoking status. In order to be included in the study, schizophrenia subjects had to have outpatient status for at least one month prior to study entry. All subjects provided written informed consent for study participation, and received nominal payment for each successful day and week of participation that was contingent on attendance only.

Figure 1.

Figure 1.

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Diagram of recruitment and enrollment of auditory training subjects (AT) and computer games control subjects (CG) from two cognitive training trials, for pooled serum and neurocognitive data.

Table 1.

Subject characteristics.

Healthy Subjects Schizophrenia Subjects
Total Sample Auditory Training Group Computer Games Group
N=53 N=90 N=47 N=43
Mean SD Mean SD Mean SD Mean SD
Female/ male 26/ 27 23/ 67 15/ 32 8/ 35
Age (y) 26.2 13.6 36.7 13.8 36.2 13.2 37.3 14.5
Education (y) 13.1 3.0 13.3 2.2 13.3 2.3 13.2 2.2
IQ 113.9 12.5 100.7 14.4 100.4 13.0 101.1 16.0
PANSS Score NA 67.8 17.0 67.7 17.8 67.8 13.4
GAF Total NA 47.0 13.7 47.4 15.1 46.5 12.0
Chlorpromazine Equivalent NA 420.1 447.9 392.7 407.5 450.2 491.4
Smokers/Non 4/ 49 41/ 49 24/ 23 17/ 26
Cigarettes/Day among smokers 7.25 5.25 18.49 10.0 18.8 11.0 18.1 8.71
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PANSS, Positive and Negative Syndrome Scale

GAF, Global Assessment of Functioning scale

2.2. Neuroplasticity-informed Computerized Cognitive Training Exercises

Software for cognitive training of auditory and verbal processing (auditory training) was provided by Posit Science Corporation. In these computerized exercises subjects were driven to make progressively more accurate distinctions about the spectro-temporal fine-structure of auditory stimuli and speech under conditions of increasing working memory load (Fisher et al., 2009). Improvements in auditory signal salience were incorporated and generalized into real-world language comprehension and working memory rehearsal. In the control condition, subjects rotated through a series of 16 enjoyable commercial computer games for the same number of hours as the auditory training subjects. Both groups rated their experiences as equally enjoyable on the 7-item subscale of interest/enjoyment from the Intrinsic Motivation Inventory (Ryan R, 1991).

2.3. Measurement of Serum Amino Acids

Serum samples for amino acid analysis were obtained from healthy volunteers at baseline and from schizophrenia participants at two time points: after completion of baseline neurocognitive testing; and ~12 weeks later, after completion of the intervention. Samples were drawn at the same time of the day (~1 PM +/−1h); the serum was separated by centrifugation and stored at −70°C. D-serine, L-serine and glycine levels were measured using HPLC (Hashimoto et al., 1992) by investigators (RP, CM and WHM) blind to the group identity of the samples.

2.4. Procedures

All schizophrenia subjects underwent cognitive and clinical testing over a 1-2 week period, followed by the first blood draw. Cognitive measures recommended by MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) were used (Kern et al., 2008; Nuechterlein et al., 2008). Raw scores were converted to z-scores using published normative data. Clinical status was assessed via the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1987) and the modified Global Assessment of Functioning scale (GAF) (Hall, 1995).

After baseline assessments, the schizophrenia subjects were stratified by age, education, gender, and symptom severity and randomly assigned to either computerized auditory system training (50 hours over ~10 weeks for the persistently ill adults; 40 hours over ~8 weeks for the recent-onset subjects) or an active computer games control group. After the intervention, all schizophrenia subjects were re-assessed on clinical and cognitive measures by personnel “blind” to group assignment. Cognitive change scores were computed as the z-score difference (post-training minus baseline scores). A Global Cognition composite score was computed as the mean of all measures of the MATRICS-defined cognitive domains.

2.5. Data analysis

The distributions of amino acid levels and of neurocognitive measures were evaluated for normalcy and missing values. Winsorized means were calculated for eight outlying amino acid values and constituted 1.5% of the total amino acid data. Cognitive measures were normally distributed after winsorising of outlying values.

Independent Samples T-tests (two-tailed) tested for group differences in demographic variables between healthy comparison and schizophrenia subjects, and between auditory training and computer games schizophrenia subgroups. Pearson correlations (2-tailed) between serum amino acids and the following variables were conducted to identify potential covariates: age, gender, education, IQ, smoking quantity (number of cigarettes per day), and symptom severity.

ANCOVA was used to examine group differences in amino acids between the healthy subjects and the schizophrenia subjects at baseline, with age, gender, IQ and smoking quantity entered as covariates. ANCOVA was used to test for auditory system training and computer games schizophrenia group differences from baseline to post-training, with age, gender, and baseline D-serine entered as covariates. Partial correlations (2-tailed) tested the association at baseline between the cognitive measures and D-serine or glycine levels (with age and gender entered as covariates), and the association of changes after intervention in cognitive measures to the changes in D-serine and glycine (with age, gender, and baseline D-serine or glycine entered as covariates).

Given our current sample size, and to reduce the risk of a type I error, correlations were conducted between D-serine and the composite cognitive measure of Global Cognition. Additionally, we conducted exploratory analysis on the composite measures of cognitive subdomains where significant or trend level group differences were found: Speed of Processing, and Verbal Learning and Memory.

3. Results

3.1. Baseline Results

Baseline amino acid levels are presented for all subject groups in Table 2. Since the schizophrenia and healthy control subjects showed an imbalance in gender, age, IQ, and smoking quantity, these measures were entered as covariates in the analyses. Serum D-serine levels were significantly lower in the schizophrenia subjects as compared to healthy subjects, with a large effect size (Cohen’s d= 8.11). L-serine levels were significantly lower in the schizophrenia subjects as compared to healthy subjects, also with a large effect size (Cohen’s d= 5.83). At baseline, D-serine in the schizophrenia group showed a significant positive correlation with Global Cognition (r= 0.37, P <0.0001). Baseline D-serine showed no significant correlations with smoking history or symptom severity (data not shown).

Table 2:

Baseline Serum Amino Acid Levels in Healthy Comparison and Schizophrenia Subjects.

Healthy Subjects Schizophrenia Subjects Statistics ANCOVA*
N= 53 N= 90
Mean SD Mean SD
D-serine (nmol/ml) 1.96 0.09 1.34 0.06 F(1,133)= 27.97 P<0.001*
L-serine (nmol/ml) 161.58 5.54 133.72 3.87 F(1,133)= 14.59 P<0.001*
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*

ANCOVA controlling for gender, age, IQ, and smoking quantity (number of cigarettes per day).

Subjects in the two schizophrenia groups, the auditory training and the computer games groups, were similar at baseline in IQ, symptoms and cognition (Table 1 and 3). Also, there were no significant differences between the two schizophrenia groups in the number of subjects taking 1st generation antipsychotics versus those taking 2nd or 3rd generation antipsychotics (X2 (1, N=74)= 0.83, P= 0.36), or in the number of subjects in each group taking antidepressants, benzodiazepines, mood stabilizers, or anticholinergic medications (Supplemental Table 1). Of note, the auditory training group included more females than the computer games group (Table 1). Although the difference was not significant (P= 0.20), the mean age and D-serine at baseline was lower in the auditory training group (Table 1 and 3). Thus, we included sex, age and baseline D-serine as covariates in the further analysis comparing the auditory training and computer games groups of schizophrenia subjects.

Table 3:

D-serine and Cognitive Performance at Baseline and After Training in Schizophrenia Subjects Participating in Either Auditory Training or Computer Games Control Condition.

Auditory Training Group
N= 47
 Computer Games Control Group
N= 43
Baseline Post-Training Baseline Post-Training
Mean SD Mean SD Mean SD Mean SD F P
D-Serine1 1.26 0.34 1.31 0.36 1.36 0.34 1.35 0.30 <0.01 0.99
Global Cognition2 −0.94 0.88 −0.81 0.90 −1.01 0.97 −1.05 0.90 4.54 0.04
Speed of Processing2 −0.65 0.86 −0.39 0.93 −0.69 0.77 −0.63 0.95 2.70 0.10
Verbal Learning and Memory2 −2.20 1.19 −1.72 1.61 −1.88 1.27 −2.06 1.50 9.51 0.003
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1

ANCOVA controlling for sex, age, and baseline D-serine or baseline glycine (df= 1.85).

2

Repeated Measures ANCOVA controlling for gender and age (df= 1.86).

3.2. Post-Intervention Results

Table 3 shows mean values at baseline and after intervention for serum D-serine and cognitive performance for the auditory training and the computer games schizophrenia groups; the subject groups did not differ in the change in D-serine. After the intervention, the two groups differed significantly in the change in Global Cognition and Verbal Learning and Memory, and at trend level in Speed of Processing. No significant group differences were found in the change in PANSS scores.

In the auditory training group, increased D-serine was significantly associated with improvements in Global Cognition (r= 0.41, P= 0.005) (Figure 2A). In contrast, no significant correlations between D-serine and change in Global Cognition were observed in the computer games control condition (Figure 2A). It is interesting to note that increased post-training D-serine was associated at trend statistical level to increased gains in Global Cognition (r= 0.26, P= 0.08) in the auditory training group but not in the control group (r= −0.03, P= 0.86). There were no significant correlations between cognitive gain and changes in L-serine levels in either subject group (data not shown).

Figure 2. Correlation between Changes in D-serine and Changes in Global Cognition and Verbal Learning and Memory.

Figure 2.

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Change in D-serine was positively correlated to z-score changes in Global Cognition (A) and Verbal Learning and Memory (B) after neuroplasticity-informed auditory training. No significant correlations were observed in the computer games control group. *Significant partial correlation (2-tailed) controlling for age, gender, and baseline D-serine, P<0.05.

Additionally, we performed an exploratory analysis to study the cognitive subdomains associated with the change in D-serine. Increased D-serine was significantly associated to improvements in Verbal Learning and Memory in the auditory training group (r= 0.54, P <0.0001) but not in the computer games control group (r= 0.15, P= 0.33) (Figure 2B); the association to change in Speed of Processing was not significant (r= 0.21, P= 0.16).

4. Discussion

To the best of our knowledge, this is the first study to investigate changes in serum D-serine levels during a cognitive enhancing treatment in schizophrenia. We found that, at baseline, serum D-serine was significantly lower in 90 schizophrenia outpatients as compared to healthy subjects, consistent with prior reports (Calcia et al., 2012; Hashimoto et al., 2003; Yamada et al., 2005). D-serine was also associated with baseline performance in Global Cognition. Although the relationship between serum D-serine and neurocognition is unknown, these results are consistent with a clinical trial of D-serine that reported a significant positive correlation between peak levels of plasma D-serine at the beginning of the trial and the final MATRICS measure of Global Cognition (Kantrowitz et al., 2010).

More importantly, we found a significant positive correlation between increases in serum D-serine and cognitive improvement in the schizophrenia subjects who performed the neuroplasticity-informed auditory training, but not in the subjects assigned to the computer games control condition. Specifically, we observed a significant association with improvement in Verbal Learning and Memory, functions that are targeted by the training. Our premise is that training-induced improvement in auditory and verbal signal salience feeds forward and facilitates adaptive neuroplastic changes in verbal cognitive systems, resulting in more efficient higher-order operations. It is possible that enhanced endogenous D-serine activity plays a role in this generalization of auditory processing efficiency to improved verbal learning and memory through mechanisms of synaptic plasticity.

4.1. D-serine, NMDA Receptor Functioning, and Successful Learning

What biological mechanisms might account for our findings? The only known site of action of endogenous D-serine in the brain is the NMDA receptor; co-activation of NMDA receptors by D-serine is a key component of synaptic plasticity (Panatier et al., 2006). Serine racemase is activated by both NMDA and non-NMDA glutamate receptors, resulting in an increase in extracellular D-serine levels (Kartvelishvily et al., 2006; Kim et al., 2005; Mustafa et al., 2009; Ribeiro et al., 2002; Schell et al., 1995). We have shown that performance of a cognitive task increases D-serine levels in the brains of rodents (Vargas-Lopes et al.). It is conceivable that intensive cognitive training and successful learning could enhance synaptic glutamatergic activity in the brain, and that this would result in increased D-serine formation. Since D-serine can cross the blood-brain barrier (Bauer et al., 2005; Hashimoto, 2002; Hashimoto and Chiba, 2004), one might observe changes in peripheral D-serine, as we have found in this study. However, the precise nature of the relationship between serum D-serine levels and D-serine signaling in the brain is unknown, and nothing in our study addresses the association between central D-serine and behavioral response. Thus, our interpretations-- while plausible-- remain highly speculative at the present time.

We have described another biological response to this method of cognitive training in persistently ill schizophrenia subjects who overlap in part with the present sample: a significant increase in serum BDNF in the auditory training group but not the computer games control group that shows no relationship to cognitive improvement (Vinogradov et al., 2009a). It appears that increased serum BDNF may reflect biological effects of the “neuroplasticity-informed” training, but that these effects may be non-specific or independent of successful learning. In contrast, in the current study we did not find a significant group-by-time interaction for serum D-serine in the two subject groups; however, we did find significant positive correlations in the auditory training subjects (but not the control subjects) between cognitive improvement and increases in D-serine. This result raises the possibility that an increase in D-serine may reflect some integral component of the brain’s ability to generate neurocognitive change and training-induced plasticity (engage in successful learning) as a result of intensive training.

4.2. Caveats and Limitations

We do not know if the D-serine findings we report here are seen only in schizophrenia subjects, or if they would also be seen in healthy subjects after cognitive training. We also cannot say whether the observed associations are found only in the kind of neuroplasticity-informed auditory training studied here, or whether they would also be found in other successful cognitive, behavioral, or pharmacological interventions. A recent study showed that serum D-serine levels increased significantly in chronic schizophrenia inpatients between the time of hospital admission and discharge, and correlated with improvement in positive symptoms; however, the D-serine levels of these schizophrenia patients at the time of the admission were elevated compared to healthy controls (Ohnuma et al., 2008). Last, in contrast to prior reports (Hashimoto et al., 2003; Kantrowitz et al., 2010) we did not find an association between D-serine levels and clinical symptoms or medication status, neither at baseline nor after training, although subjects in the present study were stable outpatients with average symptom severity in the mild range.

Limitations of this study include the unrepresentative nature of our participants, with a higher IQ and more education than the general schizophrenia population. Further, we did not control for the medication status of the subjects we studied, who were treated with a range of agents. Finally, we must consider whether the observed changes in serum D-serine could reflect processes occurring peripherally. While serine racemase is located in both brain and peripheral organs, such as kidney, liver and heart (De Miranda et al., 2000; Wolosker et al., 1999), D-serine is very low in peripheral tissues because of the presence of a large amount of the D-serine degrading enzyme D-amino acid oxidase (Nagata et al., 1989). Although this argues against a peripheral source for the D-serine changes we observed, we have no direct evidence to rule out this possibility.

Conclusion

In conclusion, we found a significant association between increases in serum D-serine levels and cognitive improvements induced by intensive neuroplasticity-informed auditory training in clinically stable schizophrenia outpatients, but not in subjects undergoing a computer games control condition. This association was not present for serum L-serine. Our data raise intriguing questions about the role of D-serine and glutamate-NMDA receptors in the response to this form of cognitive enhancement in schizophrenia. Future studies should investigate the biology of D-serine and NMDA receptor function as a possible means of augmenting the gains generated by cognitive training in individuals with schizophrenia and in other clinical populations.

Supplementary Material

Supplementary Materials

Acknowledgments

The authors gratefully acknowledge participants and their families; Prof. C. Craik for kindly allowing us to use the HPLC; and the assistance of T. Babcock, A. Lee, C. Tremblay, S. Suojanen, M. Bens, L. Reese, A.C. Rangel and A. Fantinatti.

Funding

This work was supported by the San Francisco Department of Veterans Affairs Medical Center; the National Institute of Mental Health (Grant MH073358-01 to SV) and Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ) (Grant E-26/110.305/2014 to RP). RP was a recipient of the Long-Term Fellowship from Human Frontier Science Program. CM was supported by fellowships from FAPERJ and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq). The auditory cognitive training software used in this study and all technical support were provided to us free of charge by Posit Science, Inc.

Conflict of interest

Dr. Vinogradov is a paid consultant on a BRDG-SPAN grant to Brain Plasticity Inc., a company with a commercial interest in the cognitive training software used in this study. Dr. Panizzutti is the founder of NeuroForma LTDA, a company with a financial interest in cognitive training. None of the other authors have any financial interest in Posit Science. RP, MF and SV had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Footnotes

Provide the full postal address of each affiliation, including the country name, and, if available, the e-mail address of each author.

Present/permanent address. If an author has moved since the work described in the article was done, or was visiting at the time, a ‘Present address’ (or ‘Permanent address’) may be indicated as a footnote to that author’s name. The address at which the author actually did the work must be retained as the main, affiliation address. Superscript Arabic numerals are used for such footnotes.

Abbreviations. Define abbreviations that are not standard in this field at their first occurrence in the article: in the abstract but also in the main text after it. Ensure consistency of abbreviations throughout the article.

References

  1. Bauer D, Hamacher K, Broer S, Pauleit D, Palm C, Zilles K, Coenen HH, Langen KJ, 2005. Preferred stereoselective brain uptake of d-serine--a modulator of glutamatergic neurotransmission. Nucl Med Biol 32(8), 793–797. [DOI] [PubMed] [Google Scholar]
  2. Bendikov I, Nadri C, Amar S, Panizzutti R, De Miranda J, Wolosker H, Agam G, 2007. A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia. Schizophr Res 90(1–3), 41–51. [DOI] [PubMed] [Google Scholar]
  3. Burnet PWJ, Eastwood SL, Bristow GC, Godlewska BR, Sikka P, Walker M, Harrison PJ, D-Amino acid oxidase activity and expression are increased in schizophrenia. Mol Psychiatry 13(7), 658–660. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Calcia MA, Madeira C, Alheira FV, Silva TC, Tannos FM, Vargas-Lopes C, Goldenstein N, Brasil MA, Ferreira ST, Panizzutti R, 2012. Plasma levels of D-serine in Brazilian individuals with schizophrenia. Schizophr Res 142(1–3), 83–87. [DOI] [PubMed] [Google Scholar]
  5. Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, Bougueleret L, Barry C, Tanaka H, La Rosa P, Puech A, Tahri N, Cohen-Akenine A, Delabrosse S, Lissarrague S, Picard FP, Maurice K, Essioux L, Millasseau P, Grel P, Debailleul V, Simon AM, Caterina D, Dufaure I, Malekzadeh K, Belova M, Luan JJ, Bouillot M, Sambucy JL, Primas G, Saumier M, Boubkiri N, Martin-Saumier S, Nasroune M, Peixoto H, Delaye A, Pinchot V, Bastucci M, Guillou S, Chevillon M, Sainz-Fuertes R, Meguenni S, Aurich-Costa J, Cherif D, Gimalac A, Van Duijn C, Gauvreau D, Ouellette G, Fortier I, Raelson J, Sherbatich T, Riazanskaia N, Rogaev E, Raeymaekers P, Aerssens J, Konings F, Luyten W, Macciardi F, Sham PC, Straub RE, Weinberger DR, Cohen N, Cohen D, 2002. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci U S A 99(21), 13675–13680. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Clem RL, Celikel T, Barth AL, 2008. Ongoing in Vivo Experience Triggers Synaptic Metaplasticity in the Neocortex. Science 319(5859), 101–104. [DOI] [PubMed] [Google Scholar]
  7. Coyle JT, 2006. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 26(4–6), 365–384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. De Miranda J, Santoro A, Engelender S, Wolosker H, 2000. Human serine racemase: moleular cloning, genomic organization and functional analysis. Gene 256(1–2), 183–188. [DOI] [PubMed] [Google Scholar]
  9. Detera-Wadleigh SD, McMahon FJ, 2006. G72/G30 in schizophrenia and bipolar disorder: review and meta-analysis. Biol Psychiatry 60(2), 106–114. [DOI] [PubMed] [Google Scholar]
  10. Fisher M, Holland C, Merzenich MM, Vinogradov S, 2009. Using neuroplasticity-based auditory training to improve verbal memory in schizophrenia. Am J Psychiatry 166(7), 805–811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fisher M, Holland C, Subramaniam K, Vinogradov S, 2010. Neuroplasticity-based cognitive training in schizophrenia: an interim report on the effects 6 months later. Schizophr Bull 36(4), 869–879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fisher M, Loewy R, Carter C, Lee A, Ragland JD, Niendam T, Schlosser D, Pham L, Miskovich T, Vinogradov S, 2015. Neuroplasticity-based auditory training via laptop computer improves cognition in young individuals with recent onset schizophrenia. Schizophr Bull 41(1), 250–258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fisher M, Mellon SH, Wolkowitz O, Vinogradov S, 2016. Neuroscience-informed Auditory Training in Schizophrenia: A Final Report of the Effects on Cognition and Serum Brain-Derived Neurotrophic Factor. Schizophr Res Cogn 3, 1–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hashimoto A, 2002. Effect of the intracerebroventricular and systemic administration of L-serine on the concentrations of D- and L-serine in several brain areas and periphery of rat. Brain Res 955(1–2), 214–220. [DOI] [PubMed] [Google Scholar]
  15. Hashimoto A, Chiba S, 2004. Effect of systemic administration of D-serine on the levels of D- and L-serine in several brain areas and periphery of rat. Eur J Pharmacol 495(2–3), 153–158. [DOI] [PubMed] [Google Scholar]
  16. Hashimoto A, Nishikawa T, Oka T, Takahashi K, Hayashi T, 1992. Determination of free amino acid enantiomers in rat brain and serum by high-performance liquid chromatography after derivatization with N-tert.-butyloxycarbonyl-L-cysteine and o-phthaldialdehyde. J Chromatogr 582(1–2), 41–48. [DOI] [PubMed] [Google Scholar]
  17. Hashimoto K, Engberg G, Shimizu E, Nordin C, Lindström LH, Iyo M, 2005. Reduced d-serine to total serine ratio in the cerebrospinal fluid of drug naive schizophrenic patients. Progress in Neuro-Psychopharmacology and Biological Psychiatry 29(5), 767–769. [DOI] [PubMed] [Google Scholar]
  18. Hashimoto K, Fukushima T, Shimizu E, Komatsu N, Watanabe H, Shinoda N, Nakazato M, Kumakiri C, Okada S, Hasegawa H, Imai K, Iyo M, 2003. Decreased serum levels of D-serine in patients with schizophrenia: evidence in support of the N-methyl-D-aspartate receptor hypofunction hypothesis of schizophrenia. Arch Gen Psychiatry 60(6), 572–576. [DOI] [PubMed] [Google Scholar]
  19. Heresco-Levy U, Javitt DC, Ebstein R, Vass A, Lichtenberg P, Bar G, Catinari S, Ermilov M, 2005. D-serine efficacy as add-on pharmacotherapy to risperidone and olanzapine for treatment-refractory schizophrenia. Biol Psychiatry 57(6), 577–585. [DOI] [PubMed] [Google Scholar]
  20. Hons J, Zirko R, Ulrychova M, Cermakova E, Libiger J, 2008. D-serine serum levels in patients with schizophrenia: relation to psychopathology and comparison to healthy subjects. Neuro Endocrinol Lett 29(4), 485–492. [PubMed] [Google Scholar]
  21. Kantrowitz JT, Malhotra AK, Cornblatt B, Silipo G, Balla A, Suckow RF, D’Souza C, Saksa J, Woods SW, Javitt DC, 2010. High dose D-serine in the treatment of schizophrenia. Schizophr Res 121(1–3), 125–130. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kartvelishvily E, Shleper M, Balan L, Dumin E, Wolosker H, 2006. Neuron-derived D-serine release provides a novel means to activate N-methyl-D-aspartate receptors. J Biol Chem 281(20), 14151–14162. [DOI] [PubMed] [Google Scholar]
  23. Kay SR, Fiszbein A, Opler LA, 1987. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13(2), 261–276. [DOI] [PubMed] [Google Scholar]
  24. Kern RS, Nuechterlein KH, Green MF, Baade LE, Fenton WS, Gold JM, Keefe RSE, Mesholam-Gately R, Mintz J, Seidman LJ, Stover E, Marder SR, 2008. The MATRICS Consensus Cognitive Battery, Part 2: Co-Norming and Standardization. Am J Psychiatry 165(2), 214–220. [DOI] [PubMed] [Google Scholar]
  25. Kim PM, Aizawa H, Kim PS, Huang AS, Wickramasinghe SR, Kashani AH, Barrow RK, Huganir RL, Ghosh A, Snyder SH, 2005. Serine racemase: activation by glutamate neurotransmission via glutamate receptor interacting protein and mediation of neuronal migration. Proc Natl Acad Sci U S A 102(6), 2105–2110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Madeira C, Freitas ME, Vargas-Lopes C, Wolosker H, Panizzutti R, 2008. Increased brain D-amino acid oxidase (DAAO) activity in schizophrenia. Schizophr Res 101(1–3), 76–83. [DOI] [PubMed] [Google Scholar]
  27. Mustafa AK, van Rossum DB, Patterson RL, Maag D, Ehmsen JT, Gazi SK, Chakraborty A, Barrow RK, Amzel LM, Snyder SH, 2009. Glutamatergic regulation of serine racemase via reversal of PIP2 inhibition. Proc Natl Acad Sci U S A 106(8), 2921–2926. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, Essock S, Fenton WS, Frese FJ III, Gold JM, Goldberg T, Heaton RK, Keefe RSE, Kraemer H, Mesholam-Gately R, Seidman LJ, Stover E, Weinberger DR, Young AS, Zalcman S, Marder SR, 2008. The MATRICS Consensus Cognitive Battery, Part 1: Test Selection, Reliability, and Validity. Am J Psychiatry 165(2), 203–213. [DOI] [PubMed] [Google Scholar]
  29. Ohnuma T, Sakai Y, Maeshima H, Hatano T, Hanzawa R, Abe S, Kida S, Shibata N, Suzuki T, Arai H, 2008. Changes in plasma glycine, L-serine, and D-serine levels in patients with schizophrenia as their clinical symptoms improve: results from the Juntendo University Schizophrenia Projects (JUSP). Prog Neuropsychopharmacol Biol Psychiatry 32(8), 1905–1912. [DOI] [PubMed] [Google Scholar]
  30. Ozeki Y, Sekine M, Fujii K, Watanabe T, Okayasu H, Takano Y, Shinozaki T, Aoki A, Akiyama K, Homma H, Shimoda K, 2016. Phosphoserine phosphatase activity is elevated and correlates negatively with plasma d-serine concentration in patients with schizophrenia. Psychiatry Res. [DOI] [PubMed] [Google Scholar]
  31. Panatier A, Theodosis DT, Mothet JP, Touquet B, Pollegioni L, Poulain DA, Oliet SH, 2006. Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell 125(4), 775–784. [DOI] [PubMed] [Google Scholar]
  32. Panizzutti R, Hamilton SP, Vinogradov S, 2013. Genetic correlate of cognitive training response in schizophrenia. Neuropharmacology 64, 264–267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Ribeiro CS, Reis M, Panizzutti R, de Miranda J, Wolosker H, 2002. Glial transport of the neuromodulator D-serine. Brain Res 929(2), 202–209. [DOI] [PubMed] [Google Scholar]
  34. Ryan R, K. R, Deci EL, 1991. Ego-involved persistence: when free-choice behavior is not intrinsically motivated. Motiv Emot 15, 185–205. [Google Scholar]
  35. Schell MJ, Molliver ME, Snyder SH, 1995. D-serine, an endogenous synaptic modulator: localization to astrocytes and glutamate-stimulated release. Proc Natl Acad Sci U S A 92(9), 3948–3952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tsai G, Yang P, Chung LC, Lange N, Coyle JT, 1998. D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry 44(11), 1081–1089. [DOI] [PubMed] [Google Scholar]
  37. Vargas-Lopes C, Madeira C, Kahn SA, Albino do Couto I, Bado P, Houzel JC, De Miranda J, de Freitas MS, Ferreira ST, Panizzutti R, Protein kinase C activity regulates D-serine availability in the brain. J Neurochem 116(2), 281–290. [DOI] [PubMed] [Google Scholar]
  38. Vinogradov S, Fisher M, Holland C, Shelly W, Wolkowitz O, Mellon SH, 2009a. Is serum brain-derived neurotrophic factor a biomarker for cognitive enhancement in schizophrenia? Biol Psychiatry 66(6), 549–553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Vinogradov S, Fisher M, Warm H, Holland C, Kirshner MA, Pollock BG, 2009b. The cognitive cost of anticholinergic burden: decreased response to cognitive training in schizophrenia. Am J Psychiatry 166(9), 1055–1062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Whitlock JR, Heynen AJ, Shuler MG, Bear MF, 2006. Learning induces long-term potentiation in the hippocampus. Science 313(5790), 1093–1097. [DOI] [PubMed] [Google Scholar]
  41. Wolosker H, Blackshaw S, Snyder SH, 1999. Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc Natl Acad Sci U S A 96(23), 13409–13414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Yamada K, Ohnishi T, Hashimoto K, Ohba H, Iwayama-Shigeno Y, Toyoshima M, Okuno A, Takao H, Toyota T, Minabe Y, Nakamura K, Shimizu E, Itokawa M, Mori N, Iyo M, Yoshikawa T, 2005. Identification of multiple serine racemase (SRR) mRNA isoforms and genetic analyses of SRR and DAO in schizophrenia and D-serine levels. Biol Psychiatry 57(12), 1493–1503. [DOI] [PubMed] [Google Scholar]
  43. Yamamori H, Hashimoto R, Fujita Y, Numata S, Yasuda Y, Fujimoto M, Ohi K, Umeda-Yano S, Ito A, Ohmori T, Hashimoto K, Takeda M, 2014. Changes in plasma D-serine, L-serine, and glycine levels in treatment-resistant schizophrenia before and after clozapine treatment. Neurosci Lett 582, 93–98. [DOI] [PubMed] [Google Scholar]

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