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. 2018 Mar;43(4):708-717.
doi: 10.1038/npp.2017.285. Epub 2017 Nov 20.

Effects of Amphetamine on Sensorimotor Gating and Neurocognition in Antipsychotic-Medicated Schizophrenia Patients

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Effects of Amphetamine on Sensorimotor Gating and Neurocognition in Antipsychotic-Medicated Schizophrenia Patients

Neal R Swerdlow et al. Neuropsychopharmacology. .
Free PMC article

Abstract

Prepulse inhibition (PPI) of startle is being explored both as an indicator of target engagement for, and a biomarker predicting the sensitivity to, procognitive effects of drugs. We now report the effects of the pro-attentional drug, d-amphetamine, on PPI and neurocognition in antipsychotic-medicated schizophrenia patients and healthy subjects (HS) who were also tested in a targeted cognitive training (TCT) module. 44 HS and 38 schizophrenia patients completed a double-blind, placebo-controlled crossover study of the effects of a single dose of amphetamine (10 mg po) on PPI and MATRICS Consensus Cognitive Battery (MCCB) performance; TCT results were previously reported from 60 of these subjects. Moderators predicting AMPH sensitivity were assessed, including the rs4680 single-nucleotide polymorphism for catechol-O-methyltransferase (COMT). After placebo, patients exhibited PPI deficits with 60 ms prepulse intervals; these deficits were 'rescued' by amphetamine. The magnitude of amphetamine-enhanced PPI was greater in patients than in HS (p<0.032), and was associated with positive symptoms (p<0.007), antipsychotic load (p<0.015), hedonic effects of AMPH (p<0.003), and with the presence of at least one methionine allele in rs4680 (p<0.008). No significant effects of amphetamine on MCCB performance were detected in either group, though pro-attentional effects of amphetamine in patients were associated with greater amphetamine-enhanced TCT learning. Amphetamine acutely 'normalized' PPI in antipsychotic-medicated schizophrenia patients; no concurrent acute neurocognitive changes were detected by the MCCB. Findings suggest that in the context of appropriate antipsychotic medication, a low dose of amphetamine enhances brain processes associated with higher function in schizophrenia patients, without accompanying changes in MCCB performance.

Figures

Figure 1
Figure 1
Startle reflex magnitude (a) and habituation (b) on pulse-alone trials in HS and schizophrenia (SZ) patients detected no main or interaction effects of diagnosis and amphetamine (AMPH) vs placebo (PBO). Peak reflex latency measures (c) detected known effects of trial type (facilitation by prepulses) and diagnosis (slowing in SZ patients), but no main or interaction effects of amphetamine.
Figure 2
Figure 2
(a) %PPI across 10–120-ms prepulse intervals after placebo (left) and amphetamine (right) in HS and patients. After placebo (left), patients exhibited previously reported PPI deficits at 60 ms prepulse intervals (indicated by a large oval; *p=0.05; d=0.45); amphetamine increased %PPI at 60 ms intervals in patients but not HS (right), ‘rescuing’ the PPI phenotype. The amount of amphetamine-enhanced PPI was greater in patients vs HS (b; * p<0.032), and among subjects with vs without a methionine allele at rs4680 (c; *p<0.008), and correlated significantly with the level of PANSS-positive symptoms (d; p<0.015).
Figure 3
Figure 3
(a) MCCB T-scores in HS and patients, across seven MCCB domains (A/V, attention/vigilance; RPS, reasoning and problem solving; SC, social cognition; SP, speed of processing; VisL, visual learning; VL, verbal learning; WM, working memory). Analyses confirmed significant MCCB deficits in patients vs HS, but no main or interaction effects of amphetamine. (b) Effect of amphetamine on T-scores in each domain, corrected for order effects. No significant effects of diagnosis were detected.

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