Amphetamine effects on MATRICS Consensus Cognitive Battery performance in healthy adults

Abstract

Background Cognitive deficits contribute strongly to functional disability in schizophrenia. The cost of identifying and testing candidate procognitive agents is substantial. Conceivably, candidate drugs might be first identified by positive effects on cognitive domains in sensitive subgroups of healthy subjects. Here, we examined whether the MATRICS Consensus Cognitive Battery (MCCB) detected procognitive drug effects in subgroups of healthy individuals. Methods The effects of 20 mg amphetamine (AMPH) on MCCB performance were tested in a double-blind, placebo-controlled crossover study of 60 healthy adults. AMPH effects were compared in subgroups of subjects characterized by low vs. high placebo MCCB scores, and by extreme values on personality subscales associated with schizophrenia-relevant biomarkers. Results AMPH produced autonomic and subjective effects, but did not significantly change MCCB composite scores or individual domain scores across the inclusive sample of 60 subjects. AMPH-induced MCCB changes were significantly (inversely) related to placebo MCCB performance: among individuals with lower placebo scores, AMPH enhanced performance, while among individuals with higher placebo scores, it impaired performance. A potential impact of regression to the mean was assessed, and could not be ruled out. Both placebo MCCB performance and AMPH effects on MCCB scores were significantly related to personality domains associated with schizophrenia-linked genetic- and/or neurophysiological substrates. Conclusions Among healthy adults, AMPH effects on MCCB performance were detected only among specific subgroups, and in specific cognitive domains. Strategies that utilize drug-induced changes in MCCB performance in healthy subjects to screen for candidate procognitive drugs should consider the use of “enriched” subgroups with specific neurocognitive or personality characteristics.

Animal Models of Deficient Sensorimotor Gating in Schizophrenia: Are They Still Relevant?

“…Based on these findings in HS, we assessed the effects of memantine on PPI in schizophrenia patients (Chou et al 2013a;Swerdlow et al 2016). Our findings suggest that schizophrenia patients are very sensitive to the PPI-enhancing effects of memantine (Fig.…”

“…One potential mechanism implicated in recent studies is a developmental "hypercoupling" of forebrain regions (Chambers et al 2010;Swerdlow et al 2013a, b)-including PFC and nucleus accumbens (NAC)-due to the loss of their normal innervation by the ventral hippocampus (VH) after experimentally induced VH damage. Thus, the VH innervates both the PFC and the NAC, and conditions fostering greater PFC-NAC interconnectivity might be created by NVHLs via reduced competition at a synaptic level, or by the loss of a differentiating signal normally provided by VH innervation of either structure.…”

“…Thus, the VH innervates both the PFC and the NAC, and conditions fostering greater PFC-NAC interconnectivity might be created by NVHLs via reduced competition at a synaptic level, or by the loss of a differentiating signal normally provided by VH innervation of either structure. NVHLs result in restructuring and electrophysiological changes within the PFC (Ryan et al 2013), and hyper-correlated expression of schizophrenia-linked genes in the PFC and NAC (Swerdlow et al 2013a, b). Others have reported aberrant limbic-cortical connectivity associated with both endogenous ) and drug-induced psychosis (Driesen et al 2013) in humans; similarly, excessive fronto-striatal metabolic correlation ["Brain Lock" (Schwartz 1997)] has been demonstrated in other disorders associated with the reduced PPI, such as OCD.…”

“…The ultimate test of this "PACT" predictive model will be to determine whether memantine-enhanced PPI predicts sensitivity to the ability of memantine to augment the therapeutic benefits of a cognitive intervention in these patients. We are pursuing a similar design with other PPI-enhancing drugs from different chemical classes (Chou et al 2013b;Swerdlow et al 2013a, b;Bhakta et al 2014). …”

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

“…With 7 days separating MCCB tests, drug effects on neurocognitive performance were not easily separated from experiential effects; this potential confound can impact any within-subject study of acute pro-cognitive drug effects (e.g., Chou et al 2013). While some MCCB measures have multiple versions that reduce practice effects (Nuechterlein et al 2008), these multiple versions also are a source of variability across drug tests, and the considered approach of the present study was to accept larger practice effects while carefully measuring these effects and testing ways to minimize their impact on the dependent measures.…”