It is uncertain whether older, first-generation or ‘typical’ antipsychotic medicines such as haloperidol have an effect on agitated behaviour (for example, restlessness and aggression); the effect is moderate at best. Typical antipsychotic medicines may decrease delusions and hallucinations slightly in people with dementia.
Newer, second-generation ‘atypical’ antipsychotic medicines, such as risperidone, probably reduce agitated behaviour slightly. Atypical antipsychotic medicines probably have no effect on psychotic symptoms.
Both first- and second-generation antipsychotic medicines increase the risk of drowsiness and other unwanted events. When patients’ symptoms improve after antipsychotics have been prescribed, this is probably largely due to natural improvement in symptoms over time.
What are antipsychotic medicines?
Antipsychotics are medicines prescribed to treat psychotic symptoms and severely disturbed behaviour in some mental illnesses, such as schizophrenia, bipolar disorder and severe depression. Psychotic symptoms are delusions (very strongly held beliefs in something which is not true) and hallucinations (sensing – usually seeing or hearing - things which are not really there).
Antipsychotic medicines are often divided into two groups:
1. first-generation (older) or ‘typical’ antipsychotics, for example haloperidol;
2. second-generation (newer) or ‘atypical’ antipsychotics, for example risperidone.
Both types can cause unwanted effects, such as drowsiness, movement disorders (for example, involuntary or uncontrollable movements, tremors, muscle contractions) and weight gain.
Why do people with dementia need antipsychotics?
People with dementia quite often experience hallucinations and delusions during their illness for some time. Particularly in the later stages of the illness, they may also show agitated behaviours such as restlessness, shouting out or aggression towards others. It is important to try to understand what is driving these behaviours and there are many ways to manage them which do not involve drugs. However, antipsychotic medicines have often been prescribed to people with dementia for these problems. In many countries, they are prescribed less often than in the past but are still used when the symptoms are severe.
What did we want to find out?
We wanted to know how well antipsychotic medicines reduce the severity of agitation and psychotic symptoms in people with the two commonest types of dementia, namely dementia due to Alzheimer’s disease and vascular dementia. We also wanted to know how many people experienced unwanted effects.
What did we do?
We searched for studies that investigated antipsychotic medicines currently available in the USA or European Union by comparing them with placebo (a ’dummy’ pill), for treatment of persistent agitation or psychotic symptoms. People in the studies had to have Alzheimer’s disease or vascular dementia. They could be any age and reside in a care home, a hospital, or the community. Most of the people in the studies had to be experiencing agitation (including aggression) or psychotic symptoms, or both, at the start of the study.
We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We found 24 studies with a total of 6090 people:
- six studies tested typical antipsychotics, mostly haloperidol;
- 20 studies tested atypical antipsychotics, such as risperidone, olanzapine, and aripiprazole; and
- two studies tested both typical and atypical antipsychotics.
All the studies compared antipsychotics with placebo. The people were living in institutions, hospitals, the community, or a combination of these settings.
Typical antipsychotics (haloperidol, thiothixene) compared with placebo:
- may improve symptoms of psychosis slightly (2 studies, 240 people), but we are uncertain about their effect on agitation (4 studies, 361 people);
- probably increase the risk of drowsiness (3 studies, 466 people), and movement disorders (3 studies, 467 people);
- may slightly increase the risk of serious unwanted effects (1 study, 193 people) and of death (6 studies, 578 people).
There was no evidence about the risk of non-serious and serious unwanted effects combined.
Atypical antipsychotics (risperidone, olanzapine, aripiprazole, quetiapine) compared with placebo:
- probably slightly reduce agitation (7 studies, 1971 people) and may slightly reduce aggression (1 study, 301 people), but probably make no important difference to symptoms of psychosis (12 studies, 3364 people);
- increase the risk of drowsiness (13 studies, 2878 people) and probably slightly increase movement disorders (15 studies, 4180 people);
- probably slightly increase the risk of experiencing any non-serious or serious unwanted effect combined, the risk of serious unwanted effects, and the risk of death (17 studies, 5032 people).
What are the limitations of the evidence?
Overall, our confidence in the evidence about typical antipsychotics is limited and our confidence in the evidence about atypical antipsychotics moderate. Typical antipsychotics have been investigated in just a few studies. In addition, the studies about typical and atypical antipsychotics did not always use the best methods to carry out their investigations, or did not report the results. Consequently, the effects on agitation or psychosis may have been overestimated, and the effects on adverse events underestimated.
How up to date is this evidence?
The evidence is up-to-date to 7 January 2021.
There is some evidence that typical antipsychotics might decrease agitation and psychosis slightly in patients with dementia. Atypical antipsychotics reduce agitation in dementia slightly, but their effect on psychosis in dementia is negligible. The apparent effectiveness of the drugs seen in daily practice may be explained by a favourable natural course of the symptoms, as observed in the placebo groups. Both drug classes increase the risk of somnolence and other adverse events. If antipsychotics are considered for sedation in patients with severe and dangerous symptoms, this should be discussed openly with the patient and legal representative.
Typical and atypical antipsychotics are widely used to treat agitation and psychosis in dementia. However, whether or not they are beneficial is uncertain. Some trials have yielded negative results and effectiveness may be outweighed by harms.
To assess the efficacy and safety of antipsychotics for the treatment of agitation and psychosis in people with Alzheimer's disease and vascular dementia.
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE (Ovid Sp), Embase (Ovid SP), PsycINFO (Ovid SP), CINAHL (EBSCOhost), Web of Science Core Collection (ISI Web of Science), LILACS (BIREME), ClinicalTrials.gov and the World Health Organization's meta-register, and the International Clinical Trials Registry Portal on 7 January 2021. Two review authors independently screened the title and abstract of the hits, and two review authors assessed the full text of studies that got through this screening.
We included randomised, placebo-controlled, parallel-arm trials comparing the effects of antipsychotics and placebo for the treatment of agitation or psychosis in people with dementia due to Alzheimer's disease or vascular dementia, or both, irrespective of age, severity of cognitive impairment, and setting. (The majority of) participants had to have clinically significant agitation (including aggression) or psychosis or both at baseline. We excluded studies about antipsychotics that are no longer available in the USA or EU, or that are used for emergency short-term sedation. We also excluded head-to-head trials and antipsychotic withdrawal trials.
The primary outcomes were (1) reduction in agitation or psychosis in participants with agitation or psychosis, respectively at baseline, and (2) the number of participants with adverse events: somnolence, extrapyramidal symptoms, any adverse event, any serious adverse event (SAE), and death.
Two review authors independently extracted the necessary data and assessed risk of bias with the Cochrane risk of bias tool. We calculated the pooled effect on agitation and psychosis for typical and atypical antipsychotics separately, and the pooled risk of adverse effects independent of the target symptom (agitation or psychosis). We used RevMan Web for the analyses.
The search yielded 8233 separate hits. After assessing the full-text of 35 studies, we included 24 trials that met the eligibility criteria. Six trials tested a typical antipsychotic, four for agitation and two for psychosis. Twenty trials tested an atypical antipsychotic, eight for agitation and 12 for psychosis. Two trials tested both drug types. Seventeen of 26 comparisons were performed in patients with Alzheimer’s disease specifically. The other nine comparisons also included patients with vascular dementia or mixed dementia. Together, the studies included 6090 participants (12 to 652 per study). The trials were performed in institutionalised, hospitalised and community-dwelling patients, or a combination of those.
For typical antipsychotics (e.g. haloperidol, thiothixene), we are uncertain whether these drugs improve agitation compared with placebo (standardised mean difference (SMD) -0.36, 95% confidence interval (CI) -0.57 to -0.15, 4 studies, n = 361); very low-certainty evidence, but typical antipsychotics may improve psychosis slightly (SMD -0.29, 95% CI -0.55 to -0.03, 2studies, n= 240; low-certainty evidence) compared with placebo. These drugs probably increase the risk of somnolence (risk ratio (RR) 2.62, 95% CI 1.51 to 4.56, 3 studies, n = 466; moderate-certainty evidence) and increase extrapyramidal symptoms (RR 2.26, 95% CI 1.58 to 3.23, 3 studies, n = 467; high-certainty) evidence. There was no evidence regarding the risk of any adverse event. The risks of SAEs (RR 1.32, 95% CI 0.65 to 2.66, 1 study, n = 193) and death (RR 1.46, 95% CI 0.54 to 4.00, 6 studies, n = 578) may be increased slightly, but these estimates were very imprecise, and the certainty was low. The effect estimates for haloperidol from five trials were in line with those of the drug class.
Atypical antipsychotics (e.g. risperidone, olanzapine, aripiprazole, quetiapine) probably reduce agitation slightly (SMD -0.21, 95% CI -0.30 to -0.12, 7 studies, n = 1971; moderate-certainty evidence), but probably have a negligible effect on psychosis (SMD -0.11, 95% CI -0.18 to -0.03, 12 studies, n = 3364; moderate-certainty evidence). These drugs increase the risk of somnolence (RR 1.93, 95% CI 1.57 to 2.39, 13 studies, n - 3878; high-certainty evidence) and are probably also associated with slightly increased risk of extrapyramidal symptoms (RR 1.39, 95% CI 1.14 to 1.68, 15 studies, n = 4180; moderate-certainty evidence), serious adverse events (RR 1.32, 95% CI 1.09 to 1.61, 15 studies, n= 4316; moderate-certainty evidence) and death (RR 1.36, 95% CI 0.90 to 2.05, 17 studies, n= 5032; moderate-certainty evidence), although the latter estimate was imprecise. The drugs probably have a negligible effect on the risk of any adverse event (RR 1.05, 95% CI 1.02 to 1.09, 11 studies, n = 2785; moderate-certainty evidence). The findings from seven trials for risperidone were in line with those for the drug class.