Memantine Effects On Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis

Abstract

Patients with chronic psychotic disorders (CPD) exhibit deficient sensorimotor gating (measured by prepulse inhibition (PPI) of startle) and mismatch negativity (MMN). In healthy subjects (HS), N-methyl-D-aspartate (NMDA) antagonists like memantine and ketamine increase PPI, and under some conditions, memantine enhances MMN; these findings present a challenge to understanding the basis for deficient PPI and MMN in psychotic disorders, as reduced NMDA activity is implicated in the pathogenesis of these disorders. Here we assessed for the first time the effects of memantine on PPI and MMN in CPD subjects. Baseline PPI was measured in HS and patients with a diagnosis of schizophrenia or schizoaffective disorder, depressed type. Subjects (total n=84) were then tested twice, in a double-blind crossover design, comparing either: (1) placebo vs 10 mg of memantine or (2) placebo vs 20 mg memantine. Tests included measures of acoustic startle magnitude and habituation, PPI, MMN, autonomic indices, and subjective self-rating scales. Memantine (20 mg) significantly enhanced PPI in CPD subjects, and enhanced MMN across subject groups. These effects on PPI were age dependent and most evident in older CPD patients, whereas those on MMN were most evident in younger subjects. The lower dose (10 mg) either had no detectable effect or tended to degrade these measures. The NMDA antagonist, memantine, has dose-dependent effects on preconscious, automatic measures of sensorimotor gating and auditory sensory processing that are associated with enhanced cognition and function in CPD patients. Ongoing studies will determine whether these memantine-induced changes predict acute pro-cognitive or otherwise clinically beneficial effects in CPD patients.

Figures

Figure 1

Memantine effects on prepulse inhibition: %PPI in HS and CPD patients in low dose (placebo vs 10 mg memantine; left) and high dose (placebo vs 20 mg memantine; right) groups. PPI in CPD patients was reduced by 10 mg of memantine and significantly increased by 20 mg memantine (*). CPD, chronic psychotic disorder; HS, healthy subjects.

Figure 2

Memantine (20 mg) effect on PPI—relationship to baseline and placebo PPI levels: based on our previous findings (Swerdlow et al, 2009), we assessed the relationship between memantine-enhanced PPI and baseline PPI levels, in two ways. (a) Relationship for HS (left) and CPD patients (right) divided based on their level of PPI exhibited during the screening session, about 1 week before drug testing. (b) Relationship in the same manner, except that the groups are divided based on their level of PPI exhibited in the placebo condition. In both cases, memantine enhanced PPI only among ‘low-gating' HS and CPD patients. (*) significant main effect of memantine in ‘low-gating' CPD patients; (#) significant PPI-enhancing effect of memantine in ‘low gating' HS at 30–60 ms intervals (P=0.025) after significant drug × interval interaction (P<0.005). CPD, chronic psychotic disorder; HS, healthy subjects; PPI, prepulse inhibition.

Figure 3

Memantine (20 mg) effect on PPI—relationship to age: %PPI in HS (left) and CPD patients (right) after placebo or 20 mg memantine. Memantine significantly enhanced PPI only among the older CPD patients (*). A similar, though weaker, pattern was evident among the HS group, which was significantly younger than the CPD group (‘older' HS age (range) vs ‘older' CPD patients=33.0 (30–36) vs 42.4 (39–48) years). CPD, chronic psychotic disorder; HS, healthy subjects; PPI, prepulse inhibition.

Figure 4

Memantine effect on mismatch negativity. (a) MMN (μV) in response to three different ‘oddball' stimuli, differing from standards in duration (D), pitch (P), and both duration and pitch (C (combined)). Data are shown for HS and CPD in both dose groups. Although a significant effect of diagnosis was detected for both dose groups (*), memantine effects on MMN were evident only for the 20-mg dose group (# see text). (b) ERP waveform averaged across oddball types for placebo and 20 mg memantine in age-matched subgroups of HS and CPD patients. Note comparable memantine-induced increases in MMN in both groups (main effect of memantine: P<0.04; memantine × diagnosis interaction: NS). Analyses of P3a amplitude consistently detected no significant main effects of memantine or significant two- or three-way interactions (data not shown). CPD, chronic psychotic disorder; ERP, event-related potential; HS, healthy subjects.

Figure 5

Magnitude of memantine effects across measures and age: memantine-enhanced PPI and MMN appear to reflect effects on distinct CPD subgroups. (a) Older CPD patients exhibit greater PPI-enhancing effects of 20 mg memantine. (b) Younger CPD patients exhibit greater MMN-enhancing effects of 20 mg memantine. (c) Significant negative correlation of 20 mg memantine-induced changes in PPI and MMN among 17 subjects tested on both measures. CPD, chronic psychotic disorder; MMN, mismatch negativity; PPI, prepulse inhibition.