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COMMENTARY |
a Mentrum Mental Health Care Amsterdam, Amsterdam, The Netherlands.
Rose C. van der Mast, Director of Psychiatric Residency Training, Mentrum Mental Health Care Amsterdam, 2e Constantijn Huygenstraat 37, NL-1054 AG Amsterdam, The Netherlands E-mail: ts_psych{at}wxs.nl.
Decision Editor: Jay Roberts, PhD
DELIRIUM is probably the result of dysfunction of multiple interacting neurotransmitter systems (1). Abnormalities of various neurotransmitters have been associated with, on the one hand, the divers etiologies of delirium and, on the other hand, its clinical features. Reduced cholinergic function, excess release of dopamine, norepinephrine, and glutamate, and both decreased and increased serotonergic and gamma-aminobutyric acid activity have all been implicated in the pathophysiology of delirium (2)(3). Changes in plasma levels of amino acids that are precursors of cerebral neurotransmitters may affect their function and thus contribute to the development of delirium (4).
In their interesting study in this issue, Flacker and Lipsitz found that increased availability of phenylalanine (PHE) for the brain, represented in an elevated plasma ratio of PHE to the sum of the other large neutral amino acids (oLNAA), was associated with febrile illness as well as delirium in elderly medical patients (5). In 296 patients undergoing elective cardiac surgery, a high plasma ratio of PHE/oLNAA was reported to be an independent preoperative predictor for postoperative delirium (6), in accordance with the suggestion of Flacker and Lipsitz that baseline differences in PHE/oLNAA ratios may predispose to delirium. Also, plasma levels of PHE and TRP increased for all patients during surgery, while plasma TRP and TRP/oLNAA ratios were significantly lower and PHE/oLNAA significantly higher in delirious patients compared to control patients (7).
What causes the increase of PHE in the presence of illness? In studying the pathophysiology of delirium it is necessary to take into account that risk factors for delirium (e.g., severe illness, surgery, trauma) can induce immune activation and a physical stress response comprising, among others, increased activity of the limbic-hypothalamic-pituitary-adrenocortical axis, and the occurrence of a low T3 syndrome (3). Plasma elevation of PHE may thus be explained by decreased conversion into its metabolites in the liver, because PHE hydroxylase needs tetrahydrobiopterin as a cofactor. In the presence of illness, tetrahydrobiopterin may be reduced secondary to a low T3 syndrome and decreased production of ATP (7).
It is also unclear what the exact mechanisms are that underlie the occurrence of delirium in the presence of a higher PHE/oLNAA plasma ratio. Indeed, cerebral dysfunction in the presence of increased PHE can be due to the direct neurotoxic effect of PHE and its metabolites. Although in patients with phenylketonuria, elevated plasma levels of PHE are associated with structural and functional cerebral disturbances as well as cognitive dysfunction, the increase in plasma levels of PHE found in medical patients without phenylketonuria may not reach the high levels sometimes found in patients with phenylketonuria. Moreover, the effects of different plasma levels of PHE in non-phenylketonuria patients are unknown. Another mechanism by which increased PHE possibly leads to delirium is by interfering with the uptake of the other LNAAs into the brain. High levels of PHE saturate the amino acid carrier transport system at the blood-brain barrier. Because this transport system has the highest affinity for PHE, in preference of the other LNAAs, elevations in plasma PHE may block the uptake of the other LNAAs, such as tryptophan and tyrosine, into the brain (8). Increased PHE may thus lead to disturbances in dopaminergic and serotonergic neurotransmission in the brain, even in the absence of depletion of plasma TRP or tyrosine, threatening adequate cognitive functioning.
As Flacker and Lipsitz argue, it may not be so much delirium as illness that is associated with elevated levels of PHE. However, in their study no difference was found between delirious and nondelirious patients in body mass index, maximum temperature, or number of medications. This is in contrast with our findings suggesting a relationship between delirium and poor physical condition (7). It is likely that the patient population of Flacker and Lipsitz was not sick enough, as they themselves mention. This may explain why, in addition to elevated PHE, they did not find reduced plasma levels of TRP to be related to illness and delirium. Acute stress such as febrile illness may initially cause increased plasma TRP, while prolonged stress may lead to depletion of TRP and decreased cerebral serotonergic functioning (4).
With their study, Flacker and Lipsitz contribute to the intriguing research on the pathophysiology of delirium. Their conclusion that an elevated plasma PHE/oLNAA ratio is associated with febrile illness and delirium points in the same direction as earlier studies in different patient populations. To be able to define more precisely the role of neurotransmitters in the pathophysiology of delirium, it is necessary to investigate changes in their precursor amino acids during illness and delirium, in relation to the effects of immune activation and the stress response under various acute and chronic clinical conditions.
References
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