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

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.

Modelling cognitive outcomes in the UK Biobank: education, noradrenaline and frontoparietal networks

“…However, both the executive control and default mode networks implicated by our current study are also functionally linked to the cognitive processes described by Robertson’s. Furthermore, both default mode network and executive control network are known to be modulated by the locus coeruleus-noradrenergic (LC-NE) system (Bär et al, 2016; Minzenberg et al, 2018; Robbins & Arnsten, 2009; Suttkus et al, 2021), which is pivotal to Robertson’s theory.…”

“…Furthermore, both default mode network and executive control network are known to be modulated by the locus coeruleus-noradrenergic (LC-NE) system (Bär et al, 2016;Minzenberg et al, 2018;Robbins & Arnsten, 2009;Suttkus et al, 2021), which is pivotal to Robertson's theory.…”

The role of norepinephrine in the pathophysiology of schizophrenia

“…An increasing number of studies focused on the NE system in SCZ, in particular by combining two or more of the available methods (Table 4), will give us a more complete picture of the disease. Some recent work has been done in this direction (Köhler et al, 2019;Minzenberg et al, 2018). A starting point could be to directly evaluate the triple-networks model (Fig.…”

Working memory in schizophrenia: The role of the locus coeruleus and its relation to functional brain networks

“…For example, it has been shown that drugs increasing the central NE concentration (e.g., modafinil) lead to more subjective alertness and a better performance on some attention control and working memory measures (Chamberlain & Robbins, 2013). Modafinil has also been shown to be related to the deactivation of the DMN during task performance (Minzenberg et al., 2018). Furthermore, pharmacological manipulations typically depend on baseline levels of arousal, suggesting the importance of tonic NE levels in determining the attentional state (Coull et al., 2004; Smith & Nutt, 1996).…”