Altered brainstem responses to modafinil in schizophrenia: implications for adjunctive treatment of cognition

Michael J Minzenberg,Cameron S Carter,Steffan K Soosman,Jong H Yoon

doi:10.1038/s41398-018-0104-z

Abstract

Candidate pro-cognitive drugs for schizophrenia targeting several neurochemical systems have consistently failed to demonstrate robust efficacy. It remains untested whether concurrent antipsychotic medications exert pharmacodynamic interactions that mitigate pro-cognitive action in patients. We used functional MRI (fMRI) in a randomized, double-blind, placebo-controlled within-subject crossover test of single-dose modafinil effects in 27 medicated schizophrenia patients, interrogating brainstem regions where catecholamine systems arise to innervate the cortex, to link cellular and systems-level models of cognitive control. Modafinil effects were evaluated both within this patient group and compared to a healthy subject group. Modafinil modulated activity in the locus coeruleus (LC) and ventral tegmental area (VTA) in the patient group. However, compared to the healthy comparison group, these effects were altered as a function of task demands: the control-independent drug effect on deactivation was relatively attenuated (shallower) in the LC and exaggerated (deeper) in the VTA; in contrast, again compared to the comparison group, the control-related drug effects on positive activation were attenuated in LC, VTA and the cortical cognitive control network. These altered effects in the LC and VTA were significantly and specifically associated with the degree of antagonism of alpha-2 adrenergic and dopamine-2 receptors, respectively, by concurrently prescribed antipsychotics. These sources of evidence suggest interacting effects on catecholamine neurons of chronic antipsychotic treatment, which respectively increase and decrease sustained neuronal activity in LC and VTA. This is the first direct evidence in a clinical population to suggest that antipsychotic medications alter catecholamine neuronal activity to mitigate pro-cognitive drug action on cortical circuits.

Highlights

Schizophrenia is a common, severe, high-impact disorder with cognitive deficits representing a critical determinant of clinical outcome[1,2]
Two major candidate neural targets for the remediation of prefrontal cortex (PFC) dysfunction in schizophrenia are the catecholamine systems arising from the pontine locus coeruleus (LC) and midbrain ventral tegmental area (VTA), which use norepinephrine (NE) and dopamine (DA) respectively as neurotransmitters
We found that modafinil administration leads to relative deactivation in LC and VTA in schizophrenia patients, consistent with predictions of controlindependent effects arising from NET and DAT inhibition at cell bodies in these subcortical regions (Fig. 1a)

Summary

Introduction

Schizophrenia is a common, severe, high-impact disorder with cognitive deficits representing a critical determinant of clinical outcome[1,2]. Two major candidate neural targets for the remediation of PFC dysfunction in schizophrenia are the catecholamine systems arising from the pontine locus coeruleus (LC) and midbrain ventral tegmental area (VTA), which use norepinephrine (NE) and dopamine (DA) respectively as neurotransmitters. These systems project widely throughout the cortex, and are well-suited to modulate widely-distributed neural networks such as those engaged by the PFC during higher-order cognition. This mechanism serves as an important model for the pharmacological modulation of PFC-based networks to remediate cognition in schizophrenia, and could form the basis for modafinil effects on brain function and cognition observed in other studies of schizophrenia[18]

Methods

Results

Conclusion