The following is a summary of what is known and what is not regarding the use of antipsychotic drugs in dementia-associated psychosis and agitation, based largely on the literature discussed above.
What is known
(1) Psychosis, aggression, and agitation are common problems in patients with dementia, and when severe or persistent, can cause considerable patient distress and disability, as well as caregiver strain and early institutionalization.
(2) There is no FDA-approved indication for a drug to treat psychosis or agitation in persons with dementia. However, unlabeled (or “off-label”) use of pharmacotherapy, especially antipsychotics, is common practice.
(3) More RCTs have been done in dementia patients with psychosis and/or agitation for atypical antipsychotics (aripiprazole, olanzapine, quetiapine, and risperidone) and for haloperidol than for other classes of psychotropic drugs. Most of these trials have included patients with AD or dementia of unspecified etiology. The RCTs examining antipsychotics for agitation and/or psychosis associated with dementia, in aggregate, suggest modest efficacy in symptom reduction with active treatment compared to placebo. However, several individual trials have yielded negative results. The recent CATIE-AD trial suggested that side effect burden may negate the clinical effectiveness of these agents.
(4) The incidence of mortality is significantly higher with atypical antipsychotics as a group (and that of CVAEs with several agents in this class) than with placebo in patients with dementia, based on large-scale RCTs. This has prompted the addition of an FDA black-box warning regarding these risks to the prescribing information for atypical antipsychotics. The overall risk difference is 1−2% over 8−12 weeks. These risks in addition to acute and subacute adverse effects such as excessive sedation, postural hypotension, and falls should be taken into account when considering treatment.
(5) Atypical antipsychotics are less likely than most first generation antipsychotics (especially haloperidol) to cause or exacerbate EPS and tardive dyskinesia in dementia patients. However, no other differences in efficacy or safety have been demonstrated between typical and atypical agents, although typical antipsychotics are less expensive. Individual typical or atypical drugs may have less propensity to cause certain side effects (e.g. anticholinergic, hypotensive, metabolic) compared to certain other individual agents in specific patients.
(6) The placebo response rate in RCTs testing antipsychotics in dementia is relatively high (generally 30−40%). Nonspecific therapeutic factors such as improved attention and care for patients enrolled in clinical trials likely account for a substantial portion of this improvement.
What is unknown
(1) Direct comparisons of typical and atypical antipsychotics in controlled trials in persons with dementia have been limited. As such, differential effects of these medication classes on symptom improvement and various adverse reactions (including CVAEs and death) remain undetermined. Likewise, individual antipsychotics within the same class may have differences in serious side effect profiles, but head-to-head comparisons among atypical antipsychotics have been uncommon.
(2) Given the relatively brief duration of most RCTs, the risks for CVAEs and death beyond 8−12 weeks are unknown, as are any potential long-term benefits from continued antipsychotic treatment.
(3) No specific risk or protective factors related to antipsychotic-associated CVAEs or deaths are known. It is possible that as-yet undetermined factors (e.g. medical comorbidity, etiology or stage of dementia, concomitant medications, antipsychotic dose, genetic factors) mediate risks in individual patients. The same is true regarding possible mediators/moderators of therapeutic effects.
(4) The efficacy and safety of treatment alternatives to antipsychotics are unclear. No psychotropic drug has well-established efficacy and safety in patients with dementia complicated by agitation or psychosis. The same is true for psychosocial interventions.
(5) The behavioral effects of treatments for dementia targeted at cognitive symptoms (i.e., cholinesterase inhibitors and memantine) are unclear, but appear to be modest at best, based on existing data.
(6) Whereas advances have been made in understanding the neurobiology of psychiatric complications of dementia, these findings have not yet established the most proximal causes of these symptoms. As such, specifically targeted pharmacotherapies for psychosis and agitation in dementia are unavailable; current treatments are primarily an extrapolation of treatments for related but somewhat different syndromes (e.g., schizophrenia). Future treatments more specific to underlying pathological processes in dementia may yield better results.