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

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.

Room to move: Plasticity in early auditory information processing and auditory learning in schizophrenia revealed by acute pharmacological challenge

“…By contrast, PPI has been shown to be enhanced in healthy subjects by a number of drugs with different mechanisms, including atypical antipsychotics (Swerdlow et al, 2006; Vollenweider et al, 2006), amantadine (Swerdlow et al 2002), ketamine (Duncan et al, 2001), nicotine (Hong et al, 2008) and MDMA (Vollenweider et al, 1999). We have reported that AMPH acutely enhances PPI in some subgroups of healthy individuals (Talledo et al 2009) and in schizophrenia patients (Swerdlow et al 2018). Clearly, the ability of a drug to enhance PPI in healthy subjects, absent other information, is not a sufficient basis to propose its utility in a PACT strategy.…”

Hypofunctional Dopamine Uptake and Antipsychotic Treatment-Resistant Schizophrenia

“…The antipsychotic-induced facilitation of dopamine autoinhibition, mediated by DAT blockade and D 2 autoreceptor stimulation, which may serve as an antipsychotic mechanism is depicted in Figure 3 . Although we have arrived at this hypothesis by analyzing multiple experimental observations, which sometimes lack corresponding human studies, our functional predictions on the association between extracellular dopamine and antipsychotic therapeutic responsiveness in humans and animals have been observed by a number of independent groups (35, 38, 45–48, 49, 218). In the following section, we will provide naturalistic examples of the potential importance of functional DAT to understanding antipsychotic-resistant schizophrenia.…”

Gamma oscillations predict pro-cognitive and clinical response to auditory-based cognitive training in schizophrenia

“…Electroencephalographic (EEG) biomarkers of early auditory information processing (EAIP) are promising tools in experimental medicine, which may help parse the heterogeneity of responses to TCT and other procognitive interventions 39,40 . We have demonstrated the utility of EAIP biomarkers, including ASSR, as sensitive measures of target engagement and therapeutic sensitivity in neural mechanisms relevant for learning, memory, and cognitive rehabilitation [40][41][42][43] . Findings from these experimental medicine studies suggest that assessments of baseline (e.g., event-related activity recorded prior to the initiation of TCT or other pro-cognitive interventions) and the capacity for change or "malleability" of the underlying neural circuitry in response to acute or limited "doses" of TCT may predict future TCT-related outcomes 44,45 .…”