In this study, we provide the first available evidence that fMRI can be used to demonstrate the modulatory effects of a drug with pro-cognitive potential on activity in the locus coeruleus and the ventral tegmental area, in a cognitively-impaired clinical population during cognitive performance. We found that modafinil administration leads to relative deactivation in LC and VTA in schizophrenia patients, consistent with predictions of control-independent effects arising from NET and DAT inhibition at cell bodies in these subcortical regions (Fig. 1a). Importantly, these effects were altered compared to a healthy control group, with two lines of evidence suggesting an interaction with the concurrent antipsychotic medications prescribed to these patients was responsible for these altered responses. First, relative to the healthy control group, the patients responded to modafinil with shallower deactivation in LC and deeper deactivation in VTA. This pattern is consistent with the underlying effects of chronic antipsychotic medication treatment, which lead to sustained decreases in tonic firing in the VTA, and increases in tonic firing in the LC. Second, these altered modafinil effects in the LC and VTA were significantly correlated respectively with antagonism at α 2 and D 2 receptors (despite the relatively simple measure of receptor load used here), These receptor subtypes serve an important regulatory autoreceptor-mediated inhibition of NE and DA neurons, respectively. In the patients overall, the consequences of altered responses to modafinil was that the drug was less able to positively modulate control-related increases in activity, in both these subcortical regions and in neocortical and subcortical terminal fields that support cognitive control (see Fig. 1b for hypothetical model of altered modafinil effects on catecholamine neuron activity in SZ). These findings have significant potential implications for the prospects of candidate drugs to normalize cortical dysfunction in schizophrenia, to remediate impaired cognition.

Chronic treatment with either typical or atypical antipsychotics leads to sustained increases in firing of LC neurons26,27,28,29,30. The tonic disinhibition of LC-NE neurons may then mitigate or override the feedback inhibition of LC-NE activity via cell-body autoreceptors, which would be manifest as the shallower control-independent deactivation in patients that we observed by fMRI. Given the relationship of tonic to phasic LC activity5, proxied here respectively as control-independent and control-related BOLD signal change, this increased tonic LC activity (unnormalized by modafinil) would impede relative control-related increases in LC-NE activity. We have observed just this combination of control-independent and control-related drug effects in our patient sample. It remains unclear which monoamine receptor(s) mediates the antipsychotic effect on LC activity. However, we found that the α 2 antagonist load of the concurrent antipsychotics was strongly and specifically related to impaired modafinil effects on control-related LC activity. This convergent evidence suggests that antagonism of the cell-body α 2 autoreceptor leads to impaired optimization of control-related phasic LC activity. This evidence supports the model we outlined previously, where modafinil action to inhibit NET at LC cell bodies leads to autoreceptor-mediated slowing of control-independent LC activity, allowing optimized control-related phasic LC activity to effectively modulate the cognitive control network (Fig. 1b)17.

In contrast to the activating effects on the LC, chronic antipsychotic treatment induces depolarization inactivation in VTA-DA neurons, rendering the cell-body less able to generate action potentials (reviewed in25). The relatively depolarized (but not discharging) state of antipsychotic-exposed VTA-DA neurons may then render these neurons relatively more sensitive to DAT inhibitor effects that increase DA at cell bodies. This increased sensitivity could also result from relatively more D 2 receptors in a high-affinity state, which is induced with chronic antipsychotic treatment and associated with the D 2 affinity of these medications35. One of the present findings, that the deactivating effect of modafinil on the VTA was significantly related to the D 2 load conferred by the patients’ concurrent antipsychotic medications, suggests that D 2 -receptor effects interact with modafinil responses in the VTA. Exaggerated deactivation of the VTA to modafinil could render these neurons suboptimally-responsive to control-related excitatory inputs, leading to the dissociation of cell-body vs. terminal effects of DAT inhibition (see penultimate paragraph below). This effect may also interact with underlying pathophysiology in this system, manifest in either neurochemical disturbances and/or altered responses to cognitive demands35,36,37,38,39. These considerations highlight the utility of an experimental medicine approach using in vivo methods such as fMRI, to afford direct tests in patient populations of model-driven predictions about the pharmacological modulation of these systems during cognitive processes40.

The emphasis here on cell-body effects of modafinil, and modulation of neuronal activity in the LC and VTA, is entirely compatible with models of catecholamine function that emphasize post-synaptic actions in the PFC4,6,9. Phasic activity in both VTA10 and LC neurons41,42 leads to greater neurotransmitter release compared to tonic activity, and optimizes throughput in active cortical ensembles, which may be mediated by D 1 6,7 or α 2 9 receptors. It remains likely that modafinil exerts important actions at NET in terminals in the PFC, probably to amplify the beneficial effects of cell-body modulation. The D 2 -mediated antipsychotic effects observed here could also relate to actions at DA terminals in the PFC, and α 2 antagonist effects also manifest directly at post-synaptic receptors in PFC, both leading to altered descending cortical input to the LC and VTA. Antipsychotic treatment may in fact induce a state where cell-body, terminal and post-synaptic actions are uncoupled in response to catecholamine transport inhibition. In this scenario, antipsychotic treatment leads to: (1) altered effects of pro-cognitive NET/DAT inhibition on cell-body activity (observed here), combined with (2) increased release of residual NE and DA, resulting from both terminal autoreceptor antagonism (by antipsychotics) plus NET and DAT inhibition (by modafinil), but in a manner uncoupled to cell-body activity (and the influence of control-related excitatory input to catecholamine neurons from the PFC and elsewhere), and (3) direct antagonism by antipsychotics of post-synaptic D 2 and α 2 receptors in the cortex. Thus, the circuit that maintains bidirectional influence of these subcortical neurochemical systems with cortical networks would be disrupted, unable to respond to a modulatory drug with pro-cognitive potential such as modafinil.

This study is limited by a rather modest sample size, and that the antipsychotic medication treatment was naturalistic and not randomized nor blinded, unlike the single dose of modafinil. Nevertheless, the correlations of BOLD signal change in response to modafinil exhibited specificity in their relationships with monoamine receptor-mediated effects of antipsychotics, which were predicted based on the known neurochemical effects of both modafinil and antipsychotics, and were generally not attributable to overall illness severity as measured by psychotic symptoms nor proxied by other neurochemical effects of the antipsychotics. In addition, many of these subjects were concurrently prescribed other psychotropic agents (and in a few cases, non-psychiatric medications, for other medical conditions). It remains unclear if these other medications may have contributed to the altered neural responses to modafinil observed here. Nonetheless, the pattern of observed effects fit very well the predicted pattern based on the actions of antipsychotic drugs on these systems, and how they would be expected to interact with modafinil. In addition, the supplemental medications are reasonably-representative of the adjunctive treatments that are routinely used with schizophrenia outpatients, suggesting that the observed altered brain responses are likely representative of those that may be found among schizophrenia patients more generally.

In addition, the patient sample was quite characteristic of outpatient, community-dwelling populations with schizophrenia, in terms of demographics, symptomatology and functional status. These observations suggest that the present findings may have general relevance for the future clinical management of outpatients with schizophrenia, and the potential challenge of resolving treatment for psychotic symptoms that are the clinical hallmark of the disorder, with the cognitive impairment, which is not a defining feature of schizophrenia yet remains a major determinant of functional outcome.

It is very important to emphasize that in no way do these considerations suggest that modern antipsychotic medications be abandoned or that their use be curtailed. These medications are the mainstay of treatment of all psychotic disorders, and remain the most important advance in the history of schizophrenia treatment43. It is nonetheless interesting to consider how an antipsychotic agent with relatively less catecholamine antagonist activity may mitigate these problems and serve as a better alternative, in combination with novel pro-cognitive agents, to facilitate the development of new treatments for cognition in this illness.