Acute change in mental status or delirium is multifactorial in origin. It involves both cortical and subcortical mechanisms; acetylcholine is a key neurotransmitter in its pathogenesis. Many factors increase underlying vulnerability—older age, dementia, Parkinson disease , past stroke. Many conditions act as precipitating factors—volume depletion, systemic infections, polypharmacy.

A delirious state is caused by an underlying medical condition, medication side effect, or substance intoxication or withdrawal. Most common etiologies, especially those likely to be encountered in an outpatient setting are listed in the following table.

Most cognitive impairments associated with psychotropic medications are chronic (see Appendix). Delirium is a rare side effect of psychotropic agents in the absence of toxicity. Medications associated with delirium generally have significant anticholinergic activity. Polypharmacy with multiple medications with anticholinergic or sedating properties increases the risk of delirium.

Antipsychotics associated with higher anticholinergic properties include clozapine, olanzapine, and some medications in the phenothiazine class of typical antipsychotics. Quetiapine also has some anticholinergic properties [1]. A risk factor that significantly increases chances of delirium with clozapine is combination with other anticholinergic medications [2]. Combining with benzodiazepines also increases risk [3]. Clozapine withdrawal also may cause delirium, likely from cholinergic rebound [4].

Tricyclic antidepressants also can cause delirium at therapeutic doses and the effect is related to serum level of the medication [5]. Selective serotonergic reuptake inhibitors may cause delirium via hyponatremia or the life-threatening complication of serotonin syndrome. Acute withdrawal from benzodiazepines is a well-known cause of delirium. Many antihistamines have potent anticholinergic activity and can exacerbate delirium. Diphenhydramine is a notable example. Hydroxyzine is less anticholinergic. Delirium associated with electroconvulsive therapy may be exacerbated with concurrent use of some medications, notably clozapine and lithium. Benzodiazepines may exacerbate symptoms of delirium by causing sedation.

It is to be noted that in spite of their anticholinergic and sedating effects, quetiapine, olanzapine, and benzodiazepine have some proven efficacy for treating delirium and are sometimes used for this indication.

Anticholinergic delirium is potentially life threatening. The table lists the key features.