Which is a common side effect that arises from the administration of antipsychotic medications?

Use and effectiveness

Antipsychotic drugs are currently used to treat the psychiatric and behavioral symptoms that affect elderly patients with dementia(16R) This is an unlicensed indication, but 25% of elderly patients in nursing homes receive these drugs(17c). The main conclusions from a double-blind, placebo-controlled study (CATIE-AD) in 421 out-patients were that adverse effects offset the efficacy of atypical antipsychotic drugs in managing psychosis, aggression, or agitation in patients with Alzheimer's disease, who were randomly assigned to olanzapine (mean dose 5.5 mg/day), quetiapine (57 mg/day), risperidone (mean dose 1.0 mg/day), or placebo(18C). At 12 weeks there were no significant differences with regard to the time to withdrawal for any reason: olanzapine (median 8.1 weeks), quetiapine (median 5.3 weeks), risperidone (median 7.4 weeks), and placebo (median 8.0 weeks). Although the median time to withdrawal because of lack of efficacy favored olanzapine (22 weeks) and risperidone (27 weeks) compared with quetiapine (9.1 weeks) and placebo (9.0 weeks), the time to withdrawal because of adverse events or intolerability clearly favored placebo. Overall, 24% of patients who took olanzapine, 16% of those who took quetiapine, 18% of those who took risperidone, and 5% of those who took placebo withdrew because of intolerability. There were no significant differences among the groups with regard to improvements on the Clinical Global Impression of Change scale. Moreover, neither quetiapine nor rivastigmine was effective in agitation in people with dementia in institutional care.

In a double-blind, randomized, placebo-controlled study quetiapine was associated with significant cognitive decline in 93 patients with Alzheimer's disease, dementia, and clinically significant agitation(19C)

These results coincide with those of a recent review of evidence(20R)and a recent meta-analysis(21M), although early pivotal comparisons of risperidone, haloperidol, and placebo in agitated and demented patients did not find substantial differences when the evaluation was performed at 12 months (SEDA-25, 68).

Antipsychotic drugs and stroke in patients with dementia

Different warnings to clinicians have been issued on the link between atypical antipsychotic drugs and cerebrovascular adverse events (SEDA-27, 52; SEDA-28, 59; SEDA-29, 62). The US Food and Drug Administration issued a similar warning in April 2003(22S). These warnings have led to a controversy among doctors(23r, 24R).

An early multicenter, double-blind, randomized, trial in Australia and New Zealand in 384 patients with dementia showed that risperidone caused more cerebrovascular events (9%;n=167) than placebo (1.8%;n=170) (SEDA-28, 75). Now, a meta-analysis of the effect of olanzapine for the behavioral and psychological symptoms of dementia has shown that olanzapine may also be associated with an increased risk of cerebrovascular adverse effects(25M). Nevertheless, several studies have not found any association between the use of atypical antipsychotic drugs and cerebrovascular events(26C, 27C).

Neither of two observational studies of the relation between atypical antipsychotic drugs and the risk of ischemic stroke showed a similar significant risk. In the first, a population-based retrospective cohort study, patients over 65 years with dementia who took atypical antipsychotic drugs showed no significant increase in the risk of ischemic stroke compared with those who took typical antipsychotic drugs (adjusted hazard ratio = 1.0; 95% CI = 0.8, 1.3)(28C). The numbers of new admissions for ischemic stroke were 284 in those taking atypical antipsychotic drugs (n=17845) and 227 in those taking typical antipsychotic drugs (n=14865). In the second study, data from prescription-event monitoring of olanzapine (n=8826), risperidone (n=7684), and quetiapine (n=1726) were examined(29C). The patients were mainly old (median ages 83, 81, and 69 years respectively; women 33, 74, and 70% respectively). Within 6 months of starting treatment, 10 patients had a first occurrence of a stroke or a transitory ischemic attack with olanzapine (0.1%; five fatal), 23 with risperidone (0.3%; nine fatal), and six with quetiapine (0.3%; one fatal). After adjusting for three confounders (age, sex, and indication) there were no significant differences in the relative risks of stroke between olanzapine and either risperidone or quetiapine, or between risperidone and quetiapine (RR = 1.9; 95 % CI = 0.5, 2.9 and RR = 2.1; 95% CI = 0.6, 7.6).

In another trial olanzapine 2.5–7.5 mg/day was not associated with a higher risk of adverse cardiovascular events compared to typical antipsychotic drugs (haloperidol or promazine chlorhydrate) in 346 patients aged 71–92 years with vascular dementia and behavioral problems(30C)

Antipsychotic drugs and venous thromboembolism

A possible association between venous thromboembolism and the use of antipsychotic drugs was first suggested in the 1950s after the introduction of the phenothiazines(31A). Later, a 7-fold increase in the risk of idiopathic venous thromboembolism was found among users of conventional antipsychotic drugs who were under 60 years of age and had no major risk factors(32C). More recently, a 6-month retrospective cohort study of residents of US nursing homes aged 65 years and over has shown that users of atypical but not typical antipsychotic drugs had an increased risk of hospitalization for venous thromboembolism compared with non-users(33C). The adjusted hazard ratio was 2.0 (95% CI = 1.4, 2.8) for risperidone (43 events; 3451 person-years); 1.9 (1.1, 3.3) for olanzapine (15 events; 1279 person-years); and 2.7 (1.1, 6.3) for clozapine and quetiapine (10 events; 443 person-years); there were 439 events in non-users (50 604 person-years). Since dementia was much more prevalent among users of atypical antipsychotic drugs, confounding by indication was possible; however, the findings were confirmed after excluding residents with severe cognitive decline.

Antipsychotic drugs and ventricular dysrhythmias and cardiac arrest

In a retrospective case-control study in US residents of nursing homes aged 65 years and over, conventional (adjusted OR = 1.9; 95% CI = 1.3, 2.7) but not atypical antipsychotic drugs (adjusted OR = 0.9; 95% CI = 0.6, 1.3) were associated with an increased risk of hospitalization for ventricular dysrhythmias and cardiac arrest(34C). Among residents who took conventional antipsychotic drugs, those with cardiac disease were 3.3 times (95% CI = 1.9, 5.5) more likely to be hospitalized for ventricular dysrhythmias and cardiac arrest than non-users without cardiac disease. The number of patients hospitalized for ventricular dysrhythmias and cardiac arrest (cases) was 649, and 2962 controls were selected among in-patients in the inception cohort whose primary diagnosis at discharge was septicemia, gastrointestinal hemorrhage, rectal bleeding, gastritis with bleeding, duodenitis with bleeding, or influenza.

Atypical antipsychotic drugs and the risk of death

A thorough meta-analysis of published (n=6) and unpublished (n=9) double-blind, parallel-group, randomized, placebo-controlled trials has shown an increased risk of death in patients with dementia taking atypical antipsychotic drugs(35M). There were more deaths among patients randomized to drugs (118 out of 3353; 3.5%) than those who took placebo (40 out of 1757; 2.3%) (OR = 1.5; 95% CI = 1.1, 2.2). There were no differences in dropouts.

In a recent retrospective cohort study conventional antipsychotic drugs (n=9142) were at least as likely as atypical agents (n=13748) to increase the risk of death among elderly people; accordingly, conventional drugs should not be used to replace atypical agents withdrawn in response to the FDA warning(36C). The adjusted relative risk was significantly higher with conventional antipsychotic drugs (RR = 1.4; 95% CI = 1.3, 1.5) and in all subgroups defined according to the presence or absence of dementia or nursing home residency. Hence, the US Food and Drug Administration has newly issued a warning: “All of the atypical antipsychotic drugs are approved for the treatment of schizophrenia. None, however, is approved for the treatment of behavioral disorders in patients with dementia. Because of these findings, the Agency will ask the manufacturers of these drugs to include a Boxed Warning in their labeling describing this risk and noting that these drugs are not approved for this indication. Zambia, a combination product containing olanzapine and fluoxetine, approved for the treatment of depressive episodes associated with bipolar disorder, will also be included in the request…The Agency is also considering adding a similar warning to the labeling for older antipsychotic medications because the limited data available suggest a similar increase in mortality for these drugs”(37S). Similarly, the European Agency for the Evaluation of Medicinal Products has underlined these risks in a public statement: “Neuroleptic drugs are known to be used in patients with dementia who experience psychotic symptoms and disturbed behavior. There are insufficient data to confirm any difference in the risk of mortality or cerebrovascular accidents among atypical neuroleptic drugs, including olanzapine, or between atypical and conventional neuroleptic drugs”(38S).