Several clinical outcome measures in CATIE-AD indicate that patients may benefit symptomatically from treatment with atypical antipsychotic medications. Beneficial effects of olanzapine and risperidone were apparent on the NPI total score, a summary measure of psychiatric and behavioral symptoms. Improvement on the clinician-rated CGIC global rating in the risperidone group provides convergent support for the improvements on symptom scores.
The magnitude of mean global score improvements with active medication compared to placebo was usually small. Significant group differences were not seen on the BPRS total score at the last observation, although the mixed model analysis revealed a significant effect of risperidone vs. placebo, with a larger estimated mean difference in the mixed model than was measured at the last Phase 1 observation. Some analyses revealed pairwise group differences that were near the statistical threshold for significance after adjustment for multiple comparisons, suggesting that while group differences cannot be excluded their magnitude is small. In contrast, other group differences were probably clinically meaningful. For example, the mean baseline NPI total score (36.9) was improved at the last observation in Phase 1 by 11.6 points in the risperidone group and 7.0 points in the olanzapine group, compared to 4.2 points in the placebo group. Also, the CGIC ratings at last observation in Phase 1 and at 12 weeks indicate that some individuals were likely benefiting from antipsychotic treatment. Beneficial effects of quetiapine compared to placebo did not appear on most CATIE-AD symptom outcomes, although indicates that a quetiapine effect cannot be entirely ruled out. Limited quetiapine impact on symptoms may have been due to the low dose of quetiapine prescribed. However, sedation occurred in this group at rates comparable to the other drugs (17
), suggesting at least some medication effect. Use of rescue medication (haloperidol, lorazepam) did not likely contribute to clinical outcomes, since these medications were prescribed rarely and equally across the treatment groups (17
These clinical symptom ratings in CATIE-AD complement and extend the findings from the primary effectiveness analysis that showed benefits of olanzapine and risperidone reflected in longer time to discontinuation due to lack of efficacy, which were offset by discontinuations due to adverse effects (17
). The clinical symptoms ratings reported here also show some antipsychotic efficacy during Phase 1, yet these improved last observation ratings occurred at or very near the time when the clinician decided that Phase 1 treatment was not optimal and intended to change the treatment, except for the 19% of patients who completed the entire study on Phase 1. Notably, Phase 1 discontinuations were due predominantly to insufficient efficacy. Thus, clinical symptom ratings reveal some beneficial antipsychotic effects, despite the frequent coincident decision to change treatment. This distinction suggests that clinicians were seeking a level of clinical improvement that was greater than the change detected on the clinical scales, were mindful of possible placebo assignment in Phase 1, or were balancing symptom change with other clinical considerations such as adverse effects. Treatment expectations and patient circumstances likely contributed to the perception of effectiveness. As applied to clinical practice, these findings support an individualized approach, where the value of an individual patient’s symptomatic improvement needs to be assessed in the context of that person’s particular clinical circumstances.
The analyses that used the last clinical rating in Phase 1 are conceptually different from the descriptive analyses that used scores from observed cases continuing Phase 1 treatment through week 12. The last observation analysis includes a preponderance of data from patients who, for a variety of reasons, were not doing particularly well on the assigned treatment. By contrast, the results from observed cases continuing on Phase 1 treatment apply to those who are doing reasonably well on their first prescribed medication, because Phase 1 would have ended earlier for these patients had the clinicians felt the assigned treatment was not overall effective. This is reflected in the larger improvement from baseline generally seen in all treatment groups among observed cases at week 12 compared to the last observation sample. Despite this important difference, the results using the two analytic approaches are not substantially different.
The BPRS factor scores provide a view of antipsychotic treatment effects on distinct symptoms. Patients treated with risperidone or olanzapine showed improvement on the BPRS Hostile Suspiciousness factor, which assesses hostility, aggression, mistrust, and uncooperativeness. This subscale had the highest mean score at baseline among noncognitive measures, and the mean score improved by more than 50% in the risperidone group in those continuing Phase 1 treatment at week 12. The BPRS Psychosis Factor score also improved with risperidone treatment. In contrast, antipsychotic treatment effects on the BPRS Agitation Factor score, which includes excitability, tension, and anxiety, were not as robust. This observation conforms to some clinical opinion that antipsychotics might be particularly useful for suspicious thoughts, paranoid delusions, and hostile or aggressive behaviors that occur commonly in AD.
On measures of depression or cognition, the magnitude of changes was small and there were no differences across treatments except for increased symptoms in the olanzapine group on the BPRS Withdrawn Depression factor at last observation in Phase 1. Taken together, these findings suggest that antipsychotic medication may have differential effects on specific symptoms in AD. Better understanding of specific effects can help clinicians to select optimal pharmacotherapy.
Beneficial effects were not apparent on measures of functional abilities, quality of life, or caregiving time needed. Thus, improved clinical symptoms with antipsychotic treatment did not translate to functional benefits or improved quality of life in the context of the CATIE-AD effectiveness design. This may be due to additional factors that contribute to functional disability and poor life quality, such as progression of dementia, caregiver interactions, environmental factors, and perhaps adverse effects of the drugs. Nonetheless, improved psychiatric and behavioral symptoms may be clinically meaningful for individual patients without impacting function.
There are several limitations to the study design and analyses. CATIE-AD did not follow a usual clinical efficacy trial design and while the effectiveness design has several advantages, results of these analyses should be interpreted carefully. For example, the end of Phase 1 is not defined by a specific time point, but the clinician’s judgment that continued treatment with the assigned medication is not optimal. The protocol invited medication switches based on clinical judgment and, in fact, Phase 1 treatment was often discontinued relatively quickly. In this respect, CATIE-AD results reflect clinician expectations and behaviors as well as pharmacologic efficacy. Also, the brief treatment exposure for many patients may not have captured all beneficial or adverse medication effects. Moreover, mild sedation may have contributed to behavioral improvement with antipsychotic treatment, but its specific role cannot be defined. Finally, the data analyses included many measures and comparisons, and there was no adjustment to statistical testing for the number of parameters evaluated overall.
The results presented here are predominantly group mean scores on clinical rating instruments, and this approach can obscure important treatment effects in individual patients. Subgroups of participants may respond to individual treatments particularly well or particularly poorly, as a result of distinct neurobiological factors (34
), baseline symptom patterns, or sensitivity to treatment. Additional research is needed to clarify patient- or symptom-specific responses in order to maximize benefit and minimize harm of any available treatment.
The clinical outcomes in CATIE-AD contribute to the evolving understanding of psychopharmacological interventions for psychiatric symptoms in AD. Some antipsychotic efficacy trials and these analyses indicate that clinical symptoms may improve. The extent of mean improvement on rating scales is modest, however, it is not apparent for all symptoms or in all treatment studies, and beneficial effects on mean ratings of functional ability, quality of life, or cost-effectiveness (35
) were not seen in CATIE-AD. Due to the unique design, the results of CATIE-AD are probably more generalizable to usual outpatient clinical settings than results from efficacy trials. Whether the potentially beneficial effects of symptom reduction with antipsychotic treatment outweigh other undesirable clinical or adverse effects depends on an individual patient’s circumstances, including severity of symptoms, vulnerability to adverse effects, and the effectiveness or opportunity for behavioral interventions. Additional studies to understand better the risk/benefit profile and effectiveness of specific treatments in individual patients will be valuable.