Overall, Alzheimer’s disease patients with behavioral disturbances show a steady decline over 36 weeks in most cognitive areas, regardless of antipsychotic treatment or placebo. Over the 36-week study period, these declines were not only statistically significant, but also clinically meaningful. The estimated rate of decline among placebo patients on the ADAS-Cog was similar to that seen in Alzheimer’s patients without behavioral disturbances in other trials(14
). Moreover, the rates of decline did not vary with initial level of cognitive impairment as determined by baseline MMSE score. Our method of analysis used all data points from patients who had baseline and at least one follow-up testing. However, at the later durations, there were fewer test scores mainly due to patients’ inability to perform the tests or dropping out of the study, meaning that data cannot be assumed to be missing at random. Therefore, the cognitive decline over time is likely to be greater than what we have documented (30
We evaluated the effect of treatment with atypical antipsychotics on cognitive function by comparing the weekly change (i.e., the slope of the change in cognitive function over time) among patients who had been on their current medication (or placebo) for at least two weeks prior to the date of cognitive testing. For most cognitive tests, the rate of cognitive change did not significantly differ by atypical antipsychotic. However, when the treatment groups were pooled, the group of patients on olanzapine, quetiapine, or risperidone had greater declines in cognitive function than patients on placebo on all tests except the ADAS Executive Function. As the cognitive effect of each of the medications was similar, all medications were combined and compared as a class to placebo. Combining the active treatment groups provided greater statistical power and many of the tests of cognitive functions showed significantly greater rates of decline in patients on one of the three atypical antipsychotic medications compared to patients on placebo. Over the 36 week trial period, patients on any antipsychotic had an average 2.46 point greater decline on the MMSE than placebo patients, a difference both statistically significant (p=.004) and clinically relevant.
In our comparisons of the study medications to placebo, we limited our analysis to patients who had been on the same drug for at least 2 weeks prior to the date of cognitive testing, essentially testing for a short-term effect. Alternatively, analyses could have been based on total exposure or exposure over some longer or lagged time-period. However, basing exposure on the sum over the trial would have mixed recent and distant exposures, possibly obscuring the short-term cognitive effect. Using a continuous exposure of longer than two weeks would have substantially reduced the number of patients available for analysis since many patients switched medications after relatively short exposure periods. Decline in cognitive function may be one reason patients switch medication.
This study only measured APD-effects on cognition in patients who were on medications for relatively short periods of time. We did not measure the differences in the rates of cognitive decline among patients over longer exposure periods. Therefore we cannot address the speculation whether these drugs would accelerate cognitive decline permanently or merely impair cognition during acute administration. It is also possible that this worsening of patients on antipsychotic medications would attenuate over time. It is unknown whether the greater decline in cognitive function in patients on these medications is a worsening of Alzheimer’s disease pathology or an independent effect. One possible explanation for decreased cognitive function among patients on these drugs would be sedation. However, we excluded all test dates at which the subject’s caregiver reported sedation. It is well known that antipsychotic medications degrade cognition in most non-psychotic patient groups, when used, for example, for dyskinesia control in Tourette’s and have been shown to impair aspects of cognition in schizophrenia.
Although there is strong evidence for a detrimental effect of this class of drugs on cognitive function (8
), it is not clear if this effect is equally strong in the different cognitive domains. The most significant effect that we found when comparing individual drugs to placebo was in the cognitive summary score. Since this variable combines many of the other tests, it is less subject to random fluctuations allowing differences to be recognized. If significance was not found within a given cognitive domain, however, it may not be due to absence of effect, but rather to insensitivity of the test. Patients on atypical antipsychotic improved overall clinically as evidenced by CGIC scores; however, the improvements were not statistically different from improvement seen in the placebo group.
In addition to testing a variety of cognitive domains, this study has the strength of reflecting prescribing practices with the most commonly prescribed atypical antipsychotic medications for Alzheimer’s disease. The relatively small sample size, however, with patients spread over 3 active and one placebo arm did not provide the ability to evaluate differences between the three drugs. Nevertheless, we note that the differences between the active treatments tend to be smaller than the differences between active treatment and placebo.
Some early studies and meta-analyses conducted in non-demented schizophrenic patients indicated that cognitive function may improve with the use of atypical antipsychotics compared to conventional antipsychotics (9
).Data from the CATIE schizophrenia trial, however, indicated that these improvements were small and not different from conventional antipsychotic treatment, leading the authors to conclude that these effects were likely due to the effects of expectation or practice (31
). Similarly, improvements in cognitive function reported for 104 patients with schizophrenia randomized to either olanzapine or risperidone were consistent with the improvement due to practice effects seen in 84 healthy subjects without schizophrenia (12
). The fact that the Alzheimer’s disease patients in this study did not improve cognitively with treatment may be due to their overall declining cognitive function (as seen in the full study population), vulnerability to the deleterious cognitive effects of these medications, as well as their inability to benefit from the practice improvement found in non-demented patients.
Individual trials in Alzheimer’s disease patients generally report null effects of atypical antipsychotics on MMSE scores, for the most part the only cognitive measure assessed (8
). Meta-analysis of these trials comparing olanzapine, quetiapine, risperidone, haloperidol, and aripiprazole to placebo over 6 weeks to 26 weeks (8
), in particular, including 863 patients using olanzapine, quetiapine or risperidone compared to 314 placebo patients reported a weighted mean difference for drug vs. placebo on the MMSE of 0.73 (p<.0001) with poorer scores in drug group. The additional decline in MMSE in risperidone in our study compared to placebo was statistically significant, while the declines for olanzapine and quetiapine patients were not.
Following this meta-analysis, other trials assessed cognitive change in Alzheimer’s disease patients using atypical antipsychotics. A randomized double-blind placebo-controlled trial of 80 patients found greater declines in cognitive function (measured by the Severe Impairment Battery) among those randomized to quetiapine than in those randomized to placebo (13
). Another randomized double-blind placebo-controlled trial of 268 Alzheimer’s disease patients who did not have significant behavioral problems reported greater declines on both the MMSE and ADAS-Cog among patients randomized to olanzapine than those randomized to placebo (14
). Further, the difference in ADAS-Cog scores was only significant in patients with lower baseline MMSE scores. We did not find differences in cognitive decline or treatment effect when stratified by baseline MMSE score or baseline BPRS score.
In contrast, a retrospective chart review of 58 Alzheimer’s disease patients prescribed risperidone, olanzapine or quetiapine found no decline in MMSE scores in any of the drug groups (32
). The patients in this study, however, tended to be younger and have higher baseline MMSE scores than the patients in CATIE-AD. Moreover, this chart review required patients to continue medications for 6 months and thus many patients who experienced negative cognitive effects would likely not have been included.
Our results provide additional and broad evidence that atypical antipsychoticsas compared to placebo are associated with greater rates of decline in cognitive function in Alzheimer’s disease patients with psychotic or aggressive behavior and that the magnitude of the additional declines are clinically relevant, at least as great a magnitude of the effect of cholinesterase inhibitors but in the negative direction (29
). Furthermore, these results suggest that the declines in cognitive function span a range of cognitive domains, but given our relatively limited sample size we were not able to precisely determine the difference in effect by cognitive domain. Although the sample size was not sufficient to determine if the rates of decline vary by the particular atypical antipsychotic used, the declines were evident for all three medications compared to placebo. Despite the evidence for worsening cognitive function and other adverse events with antipsychotics, improvement in psychotic and aggressive behavior may still warrant their use in individual cases (16
). To aid in choosing the best medication for a given patient, the relative adverse effects on cognitive function within this class of medication needs to be addressed in future studies, this might include assessment of attention, psychomotor, and executive function as appropriate for the level of impairment.