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Effects of acute memantine administration on MATRICS Consensus Cognitive Battery performance in psychosis: Testing an experimental medicine strategy

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Abstract

Rationale

Pro-cognitive agents for chronic psychotic disorders (CPDs) might be detected via experimental medicine models, in which neural targets engaged by the drug predict sensitivity to the drug’s pro-cognitive effects.

Objective

This study aims to use an experimental medicine model to test the hypothesis that “target engagement” predicts pro-cognitive effects of the NMDA antagonist, memantine (MEM), in CPDs.

Methods

MATRICS Consensus Cognitive Battery (MCCB) performance was assessed in CPD (n = 41) and healthy subjects (HS; n = 41) in a double-blind, randomized cross-over design of acute (single dose) MEM (placebo vs. 10 or 20 mg p.o.). Measures of prepulse inhibition (PPI) and mismatch negativity previously reported from this cohort substantiated target engagement. Biomarkers predicting MEM neurocognitive sensitivity were assessed.

Results

Testing confirmed MCCB deficits associated with CPD diagnosis, age, and anticholinergic exposure. MEM (20 mg p.o.) reduced MCCB performance in HS. To control for significant test order effects, an “order-corrected MEM effect” (OCME) was calculated. In CPD subjects, greater age, positive MEM effects on PPI, and SNP rs1337697 (within the ionotropic NMDA receptor gene, GRIN3A) predicted greater positive OCME with 20 mg MEM.

Conclusions

An experimental medicine model to assess acute pro-cognitive drug effects in CPD subjects is feasible but not without challenges. A single MEM 20 mg dose had a negative impact on neurocognition among HS. In CPD patients, age, MEM effects on PPI, and rs1337697 predicted sensitivity to the neurocognitive effects of MEM. Any potential clinical utility of these predictive markers for pro-cognitive effects of MEM in subgroups of CPD patients cannot be inferred without a validating clinical trial.

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Acknowledgments

The authors thank Ms. Sarah Lamb for her technical assistance in data collection, Ms. Michelle Breier for assistance in data collation, and Ms. Maria Bongiovanni in manuscript preparation.

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Authors and Affiliations

  1. Department of Psychiatry, UC San Diego School of Medicine, 9500 Gilman Dr., MC 0804, La Jolla, CA, 92093-0804, USA

    Savita G. Bhakta, Hsun-Hua Chou, Brinda Rana, Jo A. Talledo, Bryan Balvaneda, Laura Gaddis, Gregory A. Light & Neal R. Swerdlow

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  1. Savita G. Bhakta
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  2. Hsun-Hua Chou
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  3. Brinda Rana
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  4. Jo A. Talledo
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  6. Laura Gaddis
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  7. Gregory A. Light
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  8. Neal R. Swerdlow
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Corresponding author

Correspondence to Neal R. Swerdlow.

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Conflict of interest

Supported by MH059803, MH094320, and MH093453 (NRS, PI). SB and GAL supported by the VISN 22 MIRECC, GAL by the Sidney R. Baer Jr. Foundation and Brain & Behavior Research Foundation, SB and HHC by the Brain & Behavior Research Foundation, SB by the APF Kempf Award, and HHC by the APF/Merck Early Academic Career Award and T32-MH018399. SNP genotyping was performed by the Genomics Shared Resource supported by Roswell Park Cancer Institute and National Cancer Institute (NCI) grant P30CA016056. In the past 3 years, NRS has had support from Neurocrine, Inc. and Genco, Inc., and GAL has received support from Astellas and Forum Pharmaceuticals. Neither NRS nor GAL have ever received support from companies that develop or market memantine. The remaining authors declare no conflict of interest.

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Table S1

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Table S2

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Table S3

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Table S4

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Table S5

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Table S6

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Table S7

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Fig. S1

Effects of MEM on autonomic and subjective measures in HS and CPD subjects, assessed prior to and after MCCB administration. Values represent change from baseline (pre-pill) measures for each subject. The SRS is a visual analog scale (VAS) designed to assess general somatic and psychological symptoms, and level of consciousness (Bond et al. 1974; Bunney et al. 1999; Norris 1971). Participants rated on each 100 mm VAS the levels of several subjective states: “happy,” “drowsy,” (shown here) “queasy,” “dizzy,” and “perceptual sensitivity” that included prompts such as “Normal sounds seem unusually intense or loud” (Swerdlow et al. 2002). No statistically significant effects of drug were detected on any measure in either subject group. (GIF 107 kb)

High Resolution Image (TIF 124 kb)

Fig. S2

Example of alternative strategies to understand MEM effects on neurocognitive domains: effects of MEM on MCCB domains that incorporate a timing/speed demand (SP, AV, RP) vs. those without such a demand (WM, VL, VisL, SC) significant main effect of drug. MCCB domains were separated into those that do vs. do not include a demand for speeded response (reaction time). Among SZ patients, 10 mg MEM had no significant effect on either grouping of domains (F’s < 1), while 20 mg MEM significantly reduced performance in speed-dependent (p < 0.006) but not non-speed-dependent domains (F < 1). (PPTX 145 kb)

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Bhakta, S.G., Chou, HH., Rana, B. et al. Effects of acute memantine administration on MATRICS Consensus Cognitive Battery performance in psychosis: Testing an experimental medicine strategy. Psychopharmacology 233, 2399–2410 (2016). https://doi.org/10.1007/s00213-016-4291-0

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