**3.3.1 Imbalance in neurotransmitter systems**

### **3.3.1.1 Cholinergic deficiency**

Cholinergic neurons play an important role in cognition and memory (Kopelman, 1986). Evidence from electroencephalographic and pharmacologic studies supports the role of cholinergic deficiency in genesis of delirium. Electroencephalographic studies have shown that delirium is associated with occipital slowing, peak power and alpha decrease, delta and theta power increase and slow wave ratio increase during active delirious states (Thomas et al., 2008). Cholinergic thalamo-cortical pathways responsible for attention, alertness and vigilance regulation modulate the basic EEG alpha rhythm (Nunez et al., 2001). Centrally acting anticholinergics result in a pattern very similar to the electroencephalographic findings in delirium (Renner et al., 2005; Sloan et al., 1992).

Pharmacologic studies have shown an association between delirium and administration of anticholinergic drugs and serum anticholinergic activity (Inouye, 2006). High serum anticholinergic activity is associated with severity of delirium (Mussi et al., 1999; Trzepacz, 1999). Also, the importance of cholinergic deficiency in pathophysiology of delirium is supported by studies showing that acetylcholine neurotransmission decreases with age, which is consistent with the finding that increasing age is a risk factor for delirium (Flacker & Lipsitz, 1999). Several mechanisms can result in cholinergic deficiency and predispose to delirium, including impairment in acetylcholine synthesis and cholinergic synaptic mechanisms, ischemia and global stressors and neurotransmitter imbalance (Hshieh et al., 2008).

### **3.3.1.2 Monoamine neurotransmitter system**

Another neurotransmitter system supposed to have a role in pathogenesis of delirium is monoamine neurotransmitter system (Gaudreau & Gagnon, 2005). Dopamine, norepinephrine and serotonin have roles in arousal and sleep-wake cycle, they modulate physiological responses to stimuli (Robbins & Arnsten, 2009). This system, which is composed of three monoamine neurotransmitters, dopamine, norepinephrine and serotonin, has a balancing role for the cholinergic activity. The development of delirium involves interaction between these two neurotransmitter systems (Cole, 2004; Trzepacz & van der Mast, 2002). But instead of deficiency, dopamine excess has been reported to play a role in delirium (Moyer, 2011). It is suggested that dopamine increase during the stress of surgery can cause postoperative agitation and delusions in the patient. In laboratory studies, stress has been shown to elevate levels of mesocortical dopamine (Cassem et al., 2004). Haloperidol, a dopamine blocking agent has been used successfully to treat delirium for years (Moore & O'Keeffe, 1999).

Depending on the serotonin receptor bound, both serotonin excess and deficiency may be associated with cholinergic deficiency and predispose to delirium (Hshieh et al., 2008). Selective serotonin reuptake inhibitors like fluoxetine and buproprion have been reported to cause delirium (Chan et al., 2006). Delirium has been reported in a patient taking paroxetine preoperatively, the authors have contributed that postoperative delirium was indicating an adverse drug interaction involving, paroxetine (Stanford & Stanford, 1999).

#### **3.3.2 Neural injury, inflammation, and stress response**

Delirium has been hypothesized to result from increased release of proinflammatory cytokines in cases of trauma, infection or surgery (Eikelenboom et al., 2002; Rudolph et al.,

A Review of the Etiology Delirium 197

Brauer, C.; Morrison, R.S.; Silberzweig, S.B. & Siu, A.L. (2000). The cause of delirium in

Brouquet, A.; Cudennec, T.; Benoist, S.; Moulias, S.; Beauchet, A.; Penna, C.; Teillet, L. &

Burkhart, C.S.; Dell-Kuster, S.; Gamberini, M.; Moeckli, A.; Grapow M.; Filipovic, M.;

Burns, A.; Gallagley, A. & Byrne, J. (2004). Delirium. *Journal of Neurology, Neurosurgery and Psychiatry,* Vol.75, No. 3, (March 2004), pp. 362-367. ISSN 0022-3050. Camus, V., Gonthier, R., Dubos, G., Schwed, P., & Simeone, I. (2000). Etiologic and outcome

Cassem, N.H.; Murray, G.B.; Lafayette, J.M. & Stern, T.A. (2004). Delirious Patients. In:

Centorrino, F.; Albert, M.J.; Drago-Ferrante, G.; Koukopoulos, A.E.; Berry, J.M. &

Chan, C.H.; Liu, H.C. & Huang, M.C. (2006). Delirium associated with concomitant use

Chistyakova, Y. & Amos J (2008). Delirium associated with lamotrigine and fluoxetine

Clegg, A. & Young, J.B. (2011). Which medications to avoid in people at risk of delirium: a

Cole, M.G. (2004). Delirium in elderly patients. *The American journal of geriatric Psychiatry*,

Courtenay, W.H. (2002). Behavioural factors associated with disease: injury and

pp. 1856-1860. ISSN 0003-9926.

pp. 759-765. ISSN 0003-4932.

9887.

0749.

ISSN 0176-3679

ISSN 0002-953X.

0002-0729.

(Online).

No.4, (August 2010), pp. 555-559. ISSN 1053-0770.

02767-0. ISBN-10: 0-323-02767-9, Philedelphia.

Vol.12, No.1, pp. 7-21. ISSN 1064-7481.

patients with hip fracture. *Archives of Internal Medicine*, Vol. 160, No. 12, (June 2000),

Nordlinger, B. (2010). Impaired mobility, ASA status and administration of tramadol are risk factors for postoperative delirium in patients aged 75 years or more after major abdominal surgery. *Annals of Surgery,* Vol.251, No.4, (April 2010),

Seeberger, M.D.; Monsch, A.U.; Strebel, S.P. & Steiner, L.A. (2010). Modifiable and nonmodifiable risk factors for postoperative delirium after cardiac surgery with cardiopulmonary bypass. *Journal of Cardiothoracic and Vascular Anesthesia,* Vol.24,

profiles in hypoactive and hyperactive subtypes of delirium. *Journal of Geriatric Psychiatry and Neurology,* Vol.13, No.1, (April, 2000), pp. 38–42. ISSN 0891-

*Massachusetts General Hospital Psychiatry,* T.A. Stern ; G.L. Fricchione; N.H. Cassem; M.S. Jellinek & J.F. Rosenbaum, (Ed.) pp. 119-134, Mosby, ISBN-13: 978-0-323-

Baldessarini, R.J. (2003). Delirium during clozapine treatment: incidence and associated risk factors. *Pharmacopsychiatry* Vol.36, No.4, (July 2003), pp. 156-160.

of low-dose bupropion sustained release and fluoxetine. *Journal of Clinical Psychopharmacology*, Vol.26, No.6, (December 2006), pp. 677–679. ISSN 0271-

treatment. *The American Journal of Psychiatry* Vol.165, No.7, (July 2008), pp. 918-919.

systematic review. Age and ageing, Vol.40, No.1, (January 2011), pp.23-29. ISSN

death among men: evidence and implications for prevention. *International Journal of Men's Health*, Vol.1, No.3, (September 2002), pp. 81-142. ISSN 1933-0278

2008). Proinflammatory cytokines can affect the synthesis or release of acetylcholine, dopamine, noradrenaline and serotonin, and thereby increase the risk of delirium (Dunn, 2006). Also, these cytokines can stimulate responses from microglia, by this way cause inflammation in the brain (Dilger & Johnson, 2008). The effect of these proinflammatory cytokines do not appear to affect younger individuals with healthy brains, while the aging brain is more susceptible to the memory impairments produced by immune system activation (Staus, 2011).
