The Impact of Caffeine on Cognition in Schizophrenia

1.1 Background. Caffeine is the most used psychoactive drug in Canada, with regular consumption by 88% of the adult population and is unique because it is a "cradle-to-grave drug". In Canada, coffee is the most commonly consumed source of caffeine, while tea, chocolate and energy drinks are also significantly used. This significant rate of consumption is likely due in part to caffeine's actions on the human brain, resulting in increased arousal, elevated mood and cognitive enhancements. The effects of caffeine, at least at levels typically seen in human consumption, are primarily related to its actions at adenosine receptors. Caffeine's antagonistic effects on adenosine can be seen after even a single cup of coffee, with increased consumption resulting in increased blockade. Adenosine receptors are distributed in all brain cells, contributing to the caffeine's ability to affect a wide range of brain regions.

While levels of caffeine consumption are considered to be high in the general population, there is some evidence that they may be even higher within schizophrenia (SZ) patients. In a recent U.S. study of 146 community-dwelling individuals with SZ, daily consumption rates of caffeine were nearly double those observed in a healthy control population (471.6 mg/day vs. 254.2 mg/day; p < .001). Furthermore, 13% of the SZ population studied ingested more than 1000 mg/day of caffeine, with the highest observed intake at 2647.2 mg/day. To place this in context, Health Canada recommends adults consume no more than 400 mg of caffeine per day, and doses above 250 mg have the potential to induce symptoms of anxiety, agitation, irritability and insomnia . High doses of caffeine are particularly concerning for individuals with SZ as caffeine alters dopaminergic activity at post-synaptic neurons through its actions at adenosine A2A receptors; this enhances dopamine function, resulting in increased locomotor activity and appears to exacerbate positive symptoms, such as delusions and hallucinations . Another effect of caffeine with particular relevance to SZ involves its interaction with atypical antipsychotic drugs, such as clozapine. Both clozapine and caffeine are metabolized in the liver by the cytochrome P450 system and, in particular, the CYP1A2 isoenzyme. Competition between clozapine and caffeine has been reported to elevate antipsychotic blood levels, increasing the risk of clinically significant side effects at high dosage levels of caffeine. As such, given the high consumption levels and potential negative side effects of caffeine in SZ, it is important to understand the cortical mechanisms that underlie caffeine use.

As caffeine is mainly used because of perceived stimulant properties, including enhanced mental alertness and increased energy, research has been conducted to examine the effects of caffeine on cognitive performance in humans. These studies have identified beneficial effects of caffeine on a wide-range of cognitive processes including verbal working memory, sustained attention, and executive function. It must be noted, however, that while many studies report pro-cognitive effects of caffeine, others report no significant improvements or deficits in performance. This may be at least partially explained by evidence suggesting an 'inverted U-shaped' dose-response curve for caffeine, wherein lower doses have positive effects on performance, while high doses (i.e., above 500 mg) cause a decrease in performance.

Within the fields of attention and information processing, the electroencephalographically (EEG)-derived event-related potentials (ERPs) provide an exquisitely sensitive method of indexing cognition that can both complement and clarify behavioural observations. The ERP waveform is elicited in response to a specific stimulus, such as tones or light flashes, or cognitive events, such as recognition, decision making or response to specific stimuli events. Specifically, ERPs represent an average of the neural activity that follows the onset of a stimulus. In studies examining the effects of caffeine on the brain, EEG/ERPs appear to be preferable to neuroimaging techniques such as fMRI and PET as the vasoconstrictive nature of caffeine may confound these latter techniques, which model cortical blood flow. EEG/ERPs avoid these potential confounds and, furthermore, provide a temporal resolution far superior to some of the more sophisticated imaging techniques (i.e. PET, fMRI), making this methodology far more suitable for capturing instantaneous changes in information processing. While the literature of caffeine's effects on ERP-indexed cognitive processes is limited, there is evidence of caffeine enhancing ERPs. In one such study, not only was there quicker behavioural responding during a visual search task with caffeine (vs. placebo), but also quicker ERP measures of target detection, although caffeine did not alter ERP amplitudes.

While a hallmark characteristic of SZ is neurocognitive impairment, these deficits notably overlap with the cognitive domains that are improved by caffeine. Among the core deficts observed within SZ is a dysfunction of attentional systems, which can be observed in patients who are both acutely psychotic and in remission. Deficits of attention in SZ include both alteration of sustained attention, particularly as measured by continuous performance tasks and visual selective attention (Luck & Gold, 2008), as measured by visual search tasks. It has further been suggested that within SZ these deficits of attention contribute to dysfunction of the central executive and working memory, the limited capacity system for storing and manipulating information for short time periods (up to ~30 s), in order to carry out complex cognitive operations such as planning, reasoning, and problem solving. Impairment in working memory processes, such as those indexed by the n-back task, are a robust feature of SZ, are stable over time, and independent of psychotic symptoms.