The great Talmudic sage Hillel was once challenged to sum up his faith while standing on one foot. He replied, "That which is hateful to you, do not do to your neighbor. All the rest is commentary." If a modern-day sage of neuropsychiatry were asked to sum up the treatment of delirium, he or she might reply, "Prevent delirium in the first place, but if it occurs, treat the underlying cause and do not make matters worse. All the rest is commentary."

Indeed, any treatment for delirium that is not aimed at reversing the underlying pathophysiology could be considered a form of "cosmetic psychopharmacology," to use Peter Kramer's famous expression--or at best, a kind of symptomatic damage control. Obviously, it is far better to prevent delirium in the first place than it is to treat it after it presents, and a variety of primary and secondary delirium-prevention strategies have been devised.^1,2 Nonetheless, the effectiveness of such strategies is still unclear, and psychiatrists faced with agitated or disturbed delirious patients need to know the advantages and disadvantages of pharmacologic treatment approaches. First, though, I will briefly review some clinical aspects of delirium and a few important new research findings.

Out of the furrow

The term "delirium" is derived from the Latin, de lira, meaning "out of the furrow"--perhaps an allusion to the old Roman plow blade going "off track." Delirium may be defined as an acute or subacute disturbance of consciousness characterized by reduced ability to focus, sustain attention, or shift attention appropriately. Its hallmark, however, is a fluctuating level of consciousness, often changing from hour to hour. A prodrome of restlessness, insomnia, and nightmares sometimes precedes frank delirium. The clinical picture may sometimes include slowed or slurred speech, irritability, combative behavior, impaired short-term memory, sensory distortions, psychotic phenomena, and a reversed sleep-wake cycle.

Typically, delirium worsens at night ("sundowning"), with lucid intervals often present in the morning. It is important to realize that delirium may appear before any abnormal laboratory values are detected and may persist after the resolution of these abnormalities. Thus, the diagnosis is made on clinical, not biochemical, grounds.^3,4 Delirium may be found in as many as 11% to 16% of medical inpatients, and rates may climb to as high as 65% among elderly patients admitted for acute hospital care.⁵ Delirium may be superimposed on preexisting dementia, and it is sometimes not appreciated in elderly patients with premorbid Alzheimer disease or other dementing illnesses. Often, a sudden burst of yelling, agitation, or aggressive behavior will flag the demented patient's new onset of delirium.

I sometimes tell residents that delirium is caused by Harrison's Principles of Internal Medicine, since virtually any of the major medical disorders discussed therein may present with an "acute organic brain syndrome"--the now outmoded term for delirium. Thus, delirium may be seen as a complication of primary neurologic diseases, intercurrent infection, hypoxia, dehydration, orthopedic or cardiac surgery, or a plethora of other medical conditions.⁶ Both prescription and over-the-counter drugs are also frequent inciting factors. For all of these reasons, a careful search for the underlying causes of delirium is essential.

But is there a common pathophysiology that might unify these diverse causes of delirium? The honest answer is that we don't know. However, the leading candidate appears to be a massive failure in cholinergic neurotransmission, leading to the disruption of pathways linking cortical and subcortical structures.⁶ While this hypocholinergic hypothesis is certainly a gross oversimplification, it is both heuristic and testable. We can show, for example, that anticholinergic drugs induce or worsen delirium in human subjects and that serum anticholinergic activity is increased in patients with delirium. Conversely, physostigmine (Antilirium, others)--a reversible cholinesterase inhibitor that boosts acetylcholine--has FDA-approved labeling for the reversal of delirium due to anticholinergic toxicity. As we will see a bit later, the principle underlying this drug's action is now being exploited, using newer and better-tolerated agents.

Pharmacologic management of delirium

Nonpharmacologic approaches to the delirious patient are an important part of good care, and they include such interventions as creating a calming environment with "orienting cues," such as clocks and calendars. However, our focus is on pharmacologic interventions, which are usually required for patients with delirium whose behavior jeopardizes their safety or the safety of others (eg, patients who are pulling out their intravenous lines or assaulting others).