Despite correcting underlying medical disturbances, addressing physiologic needs, and dealing with behavioural disturbances non-pharmacologically, it may be necessary sometimes to use psychotropic medications in a rational and judicious way. As stated in the National Guidelines for Geriatric Delirium (CCSMH 2006):
“Psychotropic medications should be reserved for older persons with delirium that are in distress due to agitation or psychotic symptoms, in order to carry out essential investigations or treatment, or to prevent older delirious persons from endangering themselves or others.
In the absence of psychotic symptoms causing distress to the patient, treatment of hypoactive delirium with psychotropic medications is not recommended.
The use of psychotropic medications for the specific purpose of controlling wandering in delirium is not recommended.
Antipsychotics are the treatment of choice to manage the symptoms of delirium (with the exception of alcohol or benzodiazepine withdrawal delirium).
Haloperidol is suggested as the antipsychotic of choice based on the best available evidence to date, and atypical antipsychotics may be considered as alternative agents as they have lower rates of extra-pyramidal signs.
Benztropine should not be used prophylactically with haloperidol in the treatment of delirium.”
Major targets for pharmacological treatment are agitation or aggression, psychotic symptoms, and sleep disturbances. Reversing the sleep-wake reversal should be particularly addressed as insomnia can perpetuate delirium (Lipowski 1992). Antipsychotic medications are the treatment of choice and used short-term until the delirium subsides. The aim is to restore the dopamine-acetylcholine imbalance which is presumed to be the primary mechanism for delirium to develop, although other theories exist (Fricchione 2008, Maldonado 2008). Atypical antipsychotics have been linked to elevated mortality (Health Canada 2005) or stroke risk (Ballard 2006) in the context longer-term treatment of behavioural and psychological symptoms of dementia, but no risk data exist for shorter-term treatment of delirium. The benefits will usually outweigh the risks given the urgent nature of treating delirium, and there is a lack of suitable alternative treatment options in many cases.
Antipsychotic medications include older (“conventional”) and newer (“atypical”) agents. There are few controlled studies in treating delirium with these medications and no placebo-controlled randomized controlled trials, or RCT’s (Lonergan 2007, Seitz 2007), and the evidence that haloperidol is recommended in clinical practice guidelines (APA1999, Canadian 2006) is mostly based on clinical tradition. In one of the earliest RCT, those on haloperidol or chlorpromazine were as effectively treated but those on lorazepam monotherapy did poorly (Breitbart 1996). However, haloperidol, while devoid of hypotensive and anticholinergic effects, may not be sedating except at high doses. It is more likely to lead to extrapyramidal (Parkinsonian) side effects (EPS) especially above 4.5 mg/d in the elderly (Lonergan 2007). There is a concern with prolonged QT syndrome on the ECG and therefore ventricular arrhythmias, particularly with I.V. use, so baseline ECG’s are recommended when used. Haloperidol has been compared to risperidone and olanzapine and considered equally effective in treating delirium. Haloperidol tends to be combined with other agents such as benzodiazepines (eg: lorazepam) for desired sedative effect in the delirious person, which seems paradoxical as benzodiazepines can independently cause delirium, and contribute to ataxia and falls (Kasser 2004). Benzodiazepines should be avoided in delirium (CCSMH 2006), unless prescribed for alcohol or sedative-hypnotic withdrawal. However, benzodiazepines may help in antibiotic-induced CNS toxicity.
Conventional agents with more sedative effect that are also used include loxapine (Hewko 1996), perphenazine, methotrimeprazine (Nozinan), and chlorpromazine. On occasion, these may result in (postural) hypotension, particularly the latter two agents. Conventional agents can sometimes produce a particular type of EPS called akathisia (motor restlessness) that can add to the agitation of a delirious senior. While concerns have been raised that some of these conventional agents may have anticholinergic properties and provoke delirium, this has not been borne out clinically at the lower doses used for managing geriatric delirium (Hewko 1996), as opposed to higher doses used for those who are younger or have a chronic psychotic illness. Moreover, low dose loxapine likely has “atypical” properties (Glazer 1999, Kapur 1997) similar to some of the atypical antipsychotics. At Vancouver General Hospital’s (VGH) Consultation-Liaison Psychiatry service, there is vast experience over a 25 year period with prescribing loxapine, in preference over haloperidol for delirium, without adjunctive benzodiazepines. An open label prospective study at VGH of 32 older patients (mean age 74, loxapine mean dose= 40mg/d, range=10-100 mg/d) with post-operative delirium indicated it was safe and effective in this population (Hewko 2007), and did not lead to adverse cardiac events, even in the proportion of post-bypass patients included in the study.
Case reports and limited controlled trials of atypical antipsychotics for delirium have shown favourable responses, but administering some of these agents can be limited by a lack of a parenteral form in those refusing oral medications. Their advantage is that it is much less likely to provoke short-term reversible (parkinsonism) and long-term irreversible (tardive dyskinesia) EPS. Commonly used agents include risperidone (Ravona-Springer 1998; Han 2004), olanzapine (Skrobik 2004; Sipahimalani 1998; Breitbart 2002), and quetiapine (Torres 2001). Quetiapine in particular has both sedative and hypnotic qualities. There are very limited data with the use of aripiprazole (Straker 2006) and ziprasidone (Girard 2010). Concerns are raised that ziprasidone can prolong the QTc interval (Fricchione 2008). Atypicals are reasonable alternatives to conventionals in managing geriatric delirium (CCSMH 2006).
A list of commonly used antipsychotics with dosing ranges is reflected in Table 2. These are recommended starting doses, and subsequent doses need to be tailored for each individual. Some patients need higher doses in order for sufficient sedation. For those who are particularly sensitive to dopamine blockade, such as those with Parkinson's Disease or Lewy Body Dementia, initial choices could include quetiapine, olanzapine, or Nozinan.
Considering the route of administration, timing of administration, and length of treatment are important. Some medications can be given by intramuscular, subcutaneous, or intravenous routes to facilitate response in those refusing orally. S.C. injection is less painful compared to I.M., and seems as effective. I.V. administration is generally avoided except in critical care areas. When sleep-wake reversal occurs, or if there is “sundowning”, administering the doses towards night-time by giving b.i.d. doses at dinner and bedtime can be useful. Morning doses are usually avoided. One should treat with regular and “as needed” (prn) for as short a time as possible and one should consider tapering the dose of antipsychotic beyond 24-48 hours of when symptoms clear.
In the context of delirium, EPS should not be treated with anticholinergic agents, such as benztropine (Cogentin), as this will likely worsen delirium. Switching to an agent with less EPS potential is suggested. Prophylactic use of benztropine should never occur. Conversely, more research is needed to investigate the potential anti-delirium benefits of cholinergic agents currently in use for dementia (Mukadam 2008), and psychostimulants like Ritalin for hypoactive delirium (Gagnon 2005).
For those identified as being at high risk to develop delirium, prophylactic use of antipsychotics, cholinesterase inhibitors, or other agents prior to surgery has yielded mixed results (Kalisvaart 2005, Tabet 2009). Nevertheless, pre-operative antipsychotic use is worth considering in those who have a number of predisposing risk factors, especially if they have a known history of post-operative delirium. Non-pharmacologic multicomponent preventive interventions have shown some favourable results (Holroyd-Leduc 2010).