In older adults with MDD showing incomplete response to seqential SSRI and SNRI pharmacotherapy, remission was achieved in 50% during aripiprazole augmentation. In subjects who remitted, improvements in depression were stable throughout continuation treatment (median: 6-months). Aripiprazole was well-tolerated, with a low rate of dropout due to side effects (8%) and a high completion rate (79%), but restlessness and weight gain were not uncommon. A larger, placebo-controlled study is needed to test hypotheses related to remission, stability of remission, tolerability, safety, and outcome predictors.
We established incomplete response to SSRI and SNRI pharmacotherapy before exposing patients to aripiprazole. Even in this difficult-to-treat group, the use of aripiprazole was associated with clinically meaningful reductions in symptom burden. Two of 24 patients left the study because of apparent side effects (sedation, akathisia). Thus, overall, aripiprazole was well tolerated. Future placebo-controlled studies of adjunctive aripiprazole are needed to evaluate metabolic, neurologic, and electrocardiographic effects of aripiprazole systematically. This approach will allow simultaneous estimates of both potential benefit and risk.
Other data have suggested that sequential treatment of incomplete response in late life depression leads to a cumulative overall response rate of about 75%. That is, whether we augment with antidepressants (e.g., 13
) or switch to a different class of antidepressant (e.g., 14
), about 50% of incomplete responders show meaningful clinical improvement. In this context, adjunctive use of aripiprazole seems to be a promising strategy to evaluate. It has been shown in a placebo-controlled trial to be an effective adjunctive therapy in young and middle-aged adults with incomplete antidepressant response 7
, and our pilot data suggest but do not prove that it may be efficacious and well-tolerated in older adults who have failed sequential pharmacotherapy with SSRI and NRI agents.
Regarding the necessity of a geriatric trial, older patients with depression usually have a high burden of medical illness, are subject to extensive medication regimens, and often experience adverse drug effects 15
. In general, pharmacokinetic changes associated with aging result in higher and more variable drug concentrations in older patients. Nonetheless, available information on pharmacokinetics of antidepressants is inadequate particularly with regard to medical subgroups and potential drug interactions 16
. Because geriatric patients have been excluded from RCT’s, a placebo-controlled geriatric study is needed to determine specifically whether aging-related pharmacokinetic and pharmacodynamic factors influence treatment response or tolerability.
In future controlled evaluation of aripiprazole, the role of potential predictors and moderators of treatment response variability should be systematically evaluated. These include symptoms of anxiety (e.g., 17
), coexisting medical burden (e.g., 18
), and pharmacogenetic polymorphisms (e.g., 19
Finally, developing treatment strategies that are practicable in general medical settings, where most older Americans receive treatment for depression (if they receive it at all), is of great public health significance 1;2
. A proven pharmacologic augmentation strategy, with well documented benefit to risk ratio, would be amenable to dissemination and uptake in primary care medicine.