Serotonin and amino acids: partners in delirium pathophysiology?

Delirium may be the result of dysfunction of multiple interacting neurotransmitter systems. Changes in the levels of various amino acids being precursors of cerebral neurotransmitters may affect their function and, thus, contribute to the development of delirium. Serotonin is one of the neurotransmitters that may play an important role in medical and surgical delirium. Normal serotonin synthesis and release in the human brain is, among others, dependent on the availability of its precursor tryptophan (Trp) from blood. The essential amino acid Trp competes with the other large neutral amino acids (LNAA) tyrosine, phenylalanine, valine, leucine, and isoleucine for transport across the blood-brain barrier. This competition determines its uptake into the brain, represented by the ratio of the plasma level of Trp to the sum of the other LNAA. The plasma ratio of Trp/LNAA, plasma level of Trp, and serotonin in plasma and platelets have been used as indirect peripheral measures for central serotonergic functioning. Both increased and decreased serotonergic activity have been associated with delirium. Serotonin agonists can induce psychosis, both elevated Trp availability and increased cerebral serotonin have been associated with hepatic encephalopathy, and excess serotonergic brain activity has been related to the development of the serotonin syndrome of which delirium is a main symptom. On the other hand, alcohol withdrawal delirium, delirium in levodopa-treated Parkinson patients, and postoperative delirium have been related to reduce cerebral Trp availability from plasma suggesting diminished serotonergic function. Rick factors for delirium such as severe illness, surgery, and trauma can induce immune activation and a physical stress response comprising increased activity of the limbic-hypothalamic-pituitary-adrenocortical axis, the occurrence of a low T3 syndrome, and, possibly, changes in the permeability of the blood-brain barrier. There are indications that these changes have their effect on plasma amino acid concentrations, e.g., Trp, and multiple cerebral neurotransmitters, including serotonin. This stress response may be different depending on the stage of illness being acute or chronic. It will require further study to determine the complex influence of the stress response and immune activation on plasma amino acids, neurotransmitter function and the development of delirium, especially in the more vulnerable older patients.     

Eye tracking technology: A fresh approach in delirium assessment?

The objective of this paper is to highlight the potential role of eye tracking technology (ETT) in the assessment of delirious patients. Delirium occurs in one in five general hospital admissions (Siddiqi, 2006) and its frequency will increase as society gets older. Despite its frequency and significant independent impact upon morbidity and mortality, delirium remains under studied and is frequently missed, detected late, or misdiagnosed (Farrell & Ganzani, 1995; Inouye, 2001; Kakuma, 2003). Detection is a key target for both clinical and research efforts. Assessment of attention is key to diagnosing delirium, yet nurses and non-research medical staff often fail to correctly identify inattention (Inouye et al., ; Lemiengre et al., ; Ryan et al., 2008). Eye tracking measures have been used in a plethora of key areas of psychiatric research (Crawford et al., ; Corden, Chilvers, & Skuse, 2008; Hardin, Schroth, Pine, & Ernst, 2007; Holzman, Leonard, Proctor, & Hughes, 1973), and provide an accurate and non-invasive method in the assessment of cognitive function. The potential of ETT for direct clinical applications in the assessment of attention and comprehension, key cognitive symptoms of delirium, are promising. This paper considers potential new approaches which recent advancements in non-invasive ETT may bring to the examination and understanding of delirium.     

Can delirium relieve psychosis?

A delirium presages a poor prognosis in hospitalized patients, but an incidental delirium is a feature of some psychiatric treatments. We report five cases in which delirium preceded the relief of affective and psychotic symptoms of a major mental illness. The experience stimulated a review of the literature on delirium in psychiatric treatments. Five inpatients (aged 53 to 69 years) with an exacerbation of chronic mental illness developed deliria from medications (n = 4) and electrolyte disturbance (n = 1). The deliria were managed with medication washout or correction of electrolyte imbalance. The progress of the patients was noted clinically and summarized. The clinical signs of delirium such as confusion, disorganized speech, sleep-wake cycle changes, and hallucinations persisted for 24 to 72 hours. As the delirium cleared, psychotic and affective symptoms improved or resolved. The improvements persisted for 1 to 5 months, with low doses of medications in two of the cases. A delirium may precede clinical improvement in affective and psychotic symptoms. Historically, some treatments for mental illness induce an incidental delirium (e.g., electroconvulsive therapy [ECT] and insulin coma). Why a delirium should presage a beneficial effect on psychosis is unclear, but the emergence of delirium may herald a beneficial pathophysiology.     

Prodrome of delirium among long-term care residents: what clinical changes can be observed in the two weeks preceding a full-blown episode of delirium?

ABSTRACT Background: Delirium among long-term care (LTC) residents is frequent and is associated with increased morbidity and mortality. Identification of clinical changes during the prodromal phase of delirium could lead to prevention of a full-blown episode and perhaps limit the deleterious consequences of this syndrome. The aim of the present study was to identify clinical changes observable in the 2-week period prior to the onset of full-blown delirium. Methods: Long-term care (LTC) residents aged 65 years and over, with or without dementia were eligible for this nested case-control study. Delirium was assessed weekly over a 6-month period using the Confusion Assessment Method. Cases with incident delirium were matched by time since enrolment to one or more controls without delirium. Results: When compared to the controls, LTC residents who developed delirium (cases = 85) were more likely to have new-onset perceptual disturbances (OR = 4.75; 95% CI 1.65-13.66) and disorganized thinking (OR = 3.09; 95% CI 1.33-7.19) and a worsening of the Mini-Mental State Examination (MMSE) item measuring registration (OR = 2.59; 95% CI 1.24-5.41) during the preceding 2 weeks. However, the frequency of these changes was low. Residents with at least 3 clinical changes were more likely to develop delirium than those without any clinical change (OR = 2.52; 95% CI 1.08-5.87). Conclusions: This study provides evidence of clinical changes during the prodromal phase of delirium among LTC residents. More studies are needed to further explore the role and relevance of these clinical changes as warning signs of imminent delirium.     

Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine

This article reviews the literature relevant to improving our understanding of the neural underpinnings of delirium. That the characteristic symptoms of delirium occur as a result of a wide diversity of causes supports the concept of a "final common pathway. " What constitutes this may involve certain brain regions or circuits and certain neurotransmitters. Neuroanatomical data derived from neuroimaging and lesion reports suggest the importance of pathways in prefrontal cortex, thalamus, fusiform cortex, posterior parietal cortex, and basal ganglia. Neurotransmitters most implicated in delirium that could be candidates to mediate the characteristic symptoms of delirium, as well as the electroencephalogram changes, are acetylcholine and dopamine. Acetylcholine deficiency and dopamine excess---absolute and/or relative to each other---appear to be critical in the final common pathway. These neurotransmitters affect each other, depending on the receptor subtype, and their receptor distribution among layers of cortex in areas such as prefrontal cortex and temporal lobe suggests that cholinergic and dopaminergic neurons could interact with each other during delirium. Electroconvulsive therapy is described as a special situation in which excess dopamine and delirium may have a therapeutic effect on depression recovery, in contrast with the usual association of delirium with negative effects.     

Do motor subtypes of delirium in child and adolescent have a different clinical and phenomenological profile?

Objective

To explore the frequency of different motor subtypes of delirium in children and adolescents and to study the relationship of motor subtypes with other symptoms, etiology and outcome of delirium.

Methods

Forty-nine consecutive patients, aged 8–19 years, diagnosed as having delirium as per DSM-IV-TR were assessed on Delirium Rating Scale-Revised 98 (DRS-R-98), amended Delirium Motor Symptom Scale (DMSS), delirium etiology checklist and risk factors for delirium. Different motoric subtypes of delirium were compared with each other for symptoms of delirium as assessed by DRS-R-98, risk factors, etiology and outcome.

Results

More than half (53%) of patients were classified as having hyperactive delirium, this was followed by the mixed (26.5%) and the hypoactive (16%) subtype. When the different subtypes were compared with each other, the 3 motor subtypes did not differ from each other in terms of frequency and severity of other symptoms except for minor differences. Hallucinations are more common in patients with hyperactive and mixed subtype. There is no significant difference in the outcome of delirium across different subtypes.

Conclusion

Unlike in adults, motoric subtypes of delirium in child and adolescents do not differ from each other with respect to other symptoms, risk factors and outcome.     

The performance of the Clock Drawing Test in elderly medical inpatients: does it have utility in the identification of delirium?

The Clock Drawing Test is an often-used test for the detection of cognitive impairment, but the few studies that have evaluated its utility in delirium have produced rather inconsistent results. In a longitudinal study of delirium in elderly medical inpatients, we have investigated the relationships between the Clock Drawing Test, the presence and severity of delirium, and cognitive impairment. Using mixed linear model analysis we found that cognitive impairment was the major factor associated with low Clock Drawing Test scores (P < .0001): neither the presence nor the severity of delirium had additional significant effect on the Clock Drawing Test. Thus, we conclude that although the Clock Drawing Test is a good detector of cognitive impairment, it is not a suitable tool for detection of delirium in elderly medical inpatients.     

Educating staff working in long-term care about delirium: the Trojan horse for improving quality of care?

OBJECTIVE: This study aimed to design a multicomponent intervention to improve delirium care in long-term care facilities for older people in the UK and to identify the levers and barriers to its implementation in practice. METHODS: The research incorporated the theoretical phase and Phase 1 of the Medical Research Council's framework. We designed a multicomponent intervention based on the evidence for effective interventions for delirium and for changing practice. We refined the intervention with input from care home staff and field visits to homes. Our intervention incorporated the following features: targeting risk factors for delirium, a 'delirium practitioner' functioning as a facilitator, an education package for care home staff, staff working groups at each home to identify barriers to improving delirium care and to produce tailored solutions, a local champion identified from the working groups, consultation, liaison with other professionals, and audit or feedback. The delirium practitioner recorded her experiences of delivering the intervention in a contemporaneous log. This was analysed using framework analysis to determine the levers and barriers to implementation. RESULTS: We introduced a multicomponent intervention for delirium in six care homes in Leeds. Levers to implementation included flexibility, tailoring training to staff needs, engendering pride and ownership amongst staff, and minimising extra work. Barriers included time constraints, poor organization, and communication problems. CONCLUSION: We were able to design and deliver an evidence-based multicomponent intervention for delirium that was acceptable to staff. The next steps are to establish its feasibility and effectiveness in modifying outcomes for residents of care homes.     

Antipsychotics for the prevention and treatment of delirium in the intensive care unit: what is their role?

Delirium affects up to 80% of critically ill patients, worsens outcomes, and is frequently treated with antipsychotics despite uncertainty regarding their efficacy and safety. We identified published, English-language, randomized, controlled studies evaluating antipsychotics in ICU patients either with delirium or at risk for developing delirium. In 105 mechanically ventilated patients, the number of days spent alive without delirium or coma was similar between haloperidol (median, 14.0 days; interquartile range [IQR], 6.0-18.0 days) or ziprasidone (median, 15.0 days; IQR, 9.1-18.0 days) prophylaxis, and placebo (median, 12.5 days; IQR, 1.2-17.2 days) groups (p=0.66). Treating delirium with quetiapine, compared to placebo, in 36 ICU patients was associated with a quicker resolution of delirium (median for quetiapine, 1.0 days; IQR, 0.5-3.0 days/median for placebo, 4.5 days; IQR, 2.0-7.0 days [p=0.001]). In a third study, a similar decrease over time in delirium severity was noted between fixed-dose oral olanzapine and oral haloperidol in patients with delirium. None of the studies identified serious safety concerns with administering the antipsychotics that were studied. Published prospective, randomized clinical trials evaluating antipsychotic therapy for preventing or treating delirium in the ICU are few in number. The conclusions that can be drawn from them are limited by their heterogeneity, inconsistency in incorporating non-antipsychotic strategies known to reduce delirium or in maintaining patients in an arousable state, their size, the lack of ICU and non-ICU clinical outcomes evaluated, and the lack of placebo arms. A research framework for future evaluation of the use of antipsychotic therapy in the critically ill is proposed.     

Confusion assessment method in the diagnostics of delirium among aged hospital patients: Would it serve better in screening than as a diagnostic instrument?

BACKGROUND: The Confusion Assessment Method (CAM) is an easy, four-step algorithmic diagnostic test developed to detect delirium. OBJECTIVE: To determine how sensitive and specific the CAM is in diagnosing delirium when compared with fully operationalized criteria of delirium according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) editions III, III revised, and IV, and the International Classification of Diseases (ICD) 10th edition. METHODS: A cross-sectional study with blinded assessments was performed on consecutive elderly patients (>70 years) (n=81) in two acute geriatric hospitals in Helsinki, Finland. The sensitivity, specificity, likelihood ratios, and positive and negative predictive values of CAM were assessed with the DSM-III, DSM-III-R, DSM-IV, and ICD-10 criteria of delirium used as reference standards. RESULTS: Sensitivity rates of the CAM were proved to be only moderate (0.81-0.86) against all formal criteria of delirium. The specificity rates were lower (0.63-0.84), and far less than reported in previous studies using global assessment of the reference standard. Instead of the DSM-III-R, from which it is derived, the CAM seems more concordant with the DSM-IV criteria of delirium. The likelihood ratio for a positive CAM test was 5.06 and for a negative test 0.23, when compared with the DSM-IV. CONCLUSION: The CAM seems to be an acceptable screening instrument for delirium, but the diagnosis should be ensured according to the formal criteria of delirium, preferably by the DSM-IV.     

Polymorphisms in the NMDA subunit 2B are not associated with alcohol dependence and alcohol withdrawal–induced seizures and delirium tremens

OBJECTIVE: Ethanol-inhibited glutamatergic neurotransmission has been shown to mediate pathophysiological mechanisms in the development of alcoholism, including withdrawal symptoms. NMDA-receptor 2B (NR2B) is a subunit that confers a high sensitivity to ethanol-induced inhibition. Previously we had reported a lack of association between the single nucleotide polymorphism (SNP) rs1806201 in the NR2B gene (GRIN2B) and alcoholism. Shortly thereafter, an association between the polymorphism and early-onset alcoholism has been reported. One aim of the present study was to test whether the association between the GRIN2B polymorphism rs1806201 and early-onset alcoholism can be replicated in a larger sample. Moreover, we hypothesized that another genetic variation within GRIN2B (rs1806191) may have an effect in the etiology of alcoholism or withdrawal-related traits. METHODS: We extended our original study sample to a size of 377 patients and 464 healthy volunteers and performed a replication study, including the second GRIN2B SNP. Associations between allele, genotype and haplotype frequencies of the two polymorphisms and alcoholism as well as with patients' phenotypes were investigated. RESULTS: No associations were found between any of the two polymorphisms, tested individually or as haplotypes, and alcoholism, respectively withdrawal-related traits. CONCLUSION: Neither the analyzed SNPs nor any of their haplotypes likely modify susceptibility to alcohol dependence or withdrawal-related phenotypes.     

Delirium phenomenology: what can we learn from the symptoms of delirium?

OBJECTIVES: This review focuses on phenomenological studies of delirium, including subsyndromal and prodromal concepts, and their relevance to other elements of clinical profile. METHODS: A Medline search using the keywords delirium, phenomenology, and symptoms for new data articles published in English between 1998 and 2008 was utilized. The search was supplemented by additional material not identified by Medline but known to the authors. RESULTS: Understanding of prodromal and subsyndromal concepts is still in its infancy. The characteristic profile can differentiate delirium from other neuropsychiatric disorders. Clinical (motoric) subtyping holds potential but more consistent methods are needed. Studies are almost entirely cross-sectional in design and generally lack comprehensive symptom assessment. Multiple assessment tools are available but are oriented towards hyperactive features and few have demonstrated ability to distinguish delirium from dementia. There is insufficient evidence linking specific phenomenology with etiology, pathophysiology, management, course, and outcome. CONCLUSIONS: Despite the major advancements of the past decade in many aspects of delirium research, further phenomenological work is crucial to targeting studies of causation, pathophysiology, treatment, and prognosis. We identified eight key areas for future studies.