Seven controlled trials (n=2,314) evaluated efficacy and short-term safety. Long-term safety was evaluated using data from one manufacturer-conducted review of data from placebo-controlled trials (n=3,486), one FDA report based on an analysis of 17 placebo-controlled trials, two observational studies, one retrospective cohort study (n=11,400) and one-case control study (n stated where possible).
Atypical antipsychotics versus placebo.
Olanzapine: two studies were identified. One good quality double-blind randomised controlled trials (RCT) reported a significantly greater improvement in NPI-NH Core Total at 6 weeks in patients taking 5 or 10 mg olanzapine compared with placebo but reported no difference between 15 mg olanzapine and placebo. One fair-quality double-blind RCT reported a significantly greater improvement in NPI-NH Psychosis Total score at 10 weeks in patients taking 7.5 mg olanzapine compared with placebo, but reported no difference between other doses of olanzapine (1.0, 2.5 and 5.0 mg) and placebo. It also reported a significantly greater improvement in the Clinical Global Impression of Change (CGI-C) in patients taking 2.5 mg olanzapine compared with placebo but not for other doses of olanzapine versus placebo.
Risperidone: two studies were identified. One fair-quality double-blind RCT reported a significantly greater improvement in BEHAVE-AD (most subscales of this scale) and the CMAI (total and aggressive subscales) in patients taking a final mean dose of 0.95 mg risperidone compared with placebo. One fair-quality RCT reported a significantly greater improvement in BEHAVE-AD in patients taking 1.0 and 2.0 mg risperidone compared with placebo, but reported no difference between 0.5 mg risperidone and placebo.
Quetiapine and aripiprazole: only limited evidence was found.
Short-term adverse effects.
There were generally no differences in EPS between olanzapine and risperidone compared with placebo. Exceptions were an increase in the ESRS with risperidone 2 mg (one study) and a significantly higher rate of total withdrawals and withdrawals due to adverse events for 2 mg risperidone compared with placebo (one study). Withdrawal rates were high in all treatment groups including placebo (range: 20 to 42%).
Atypical versus typical antipsychotics.
Risperidone versus haloperidol: three studies were identified. Two fair-quality parallel-group trials reported no significant differences on the CMAI or BEHAVE-AD scales at 12 weeks between risperidone and haloperidol (0.5 to 2.0 mg for both drugs). One fair-quality crossover RCT that did not assess the carry-over effect reported significantly greater improvements on the CMAI, CGI-C, BEHAVE-AD scales at 8 weeks in patients taking risperidone (mean 0.80 mg) compared with haloperidol (mean 0.83 mg).
Short-term adverse events (three studies).
One study reported significant improvement in EPS in patients taking risperidone (mean dose 1.1 mg) compared with haloperidol (mean dose 1.2 mg). The second study reported improvements on some measures (ESRS total and parkinsonism subscales) for risperidone (mean 0.83 mg) compared with haloperidol (mean 0.80 mg) but not others (dyskinetic movement and dystonia subscales). The third study did not report comparative results. There were no significant differences between risperidone and haloperidol in total withdrawals or withdrawals due to adverse events.
Atypical antipsychotics versus each other.
Risperidone versus olanzapine: two studies were identified. Two small poor-quality studies reported no differences on any outcome (including withdrawal and withdrawal due to adverse events) between risperidone and olanzapine at 2 weeks and 2 months.
One manufacturer-conducted review of data from placebo-controlled trials reported that cardiovascular adverse events occurred in 1.3% (15 of 1,778) patients taking risperidone compared with 0.4% (2 of 478) taking placebo, and in 4% (29 of 764) patients taking olanzapine compared with 2% (7 of 466) taking placebo. The review authors stated that there was insufficient information available to assess the appropriateness of combining studies.
One FDA report based on an analysis of 17 placebo-controlled trials evaluating olanzapine, aripiprazole, risperidone and quetiapine reported an increased death rate with the atypical antipsychotic (1.6 to 1.7 times that of placebo).
Two observational studies reported no increase in the risk of stroke (one study) or ventricular arrhythmia or cardiac arrest (one study) associated with atypical antipsychotics. One good-quality retrospective cohort study reported no difference in the crude or adjusted stroke rate between patients given typical antipsychotics, risperidone and olanzapine. One fair-quality case-control study reported that the risk of hospitalisation for ventricular arrhythmia or cardiac arrest was significantly higher for users of typical antipsychotics compared with non-users, but there was no difference between users of atypical antipsychotics and non-users; the analysis was adjusted for risk factors.