A study suggests that aripiprazole augmentation may be an effective strategy for treating major depression in older adults.
The article has generated a lot of interest because of evidence suggesting that late life major depression may be different from major depression in early adulthood.
Cognitive impairment, including memory troubles and trouble with planning and decision making (executive function), seems to be more severe in older adults with depression. And brain scans more often show abnormalities in white matter in late life depression.
And these cognitive differences tend to predict worse outcomes when treating major depression.
There are major differences in how medications are metabolized and how they affect us as we age, so we can’t simply assume that the results of trials in younger adults can be applied to older adults.
However, in a systematic review of the literature done in 2011, there were no double-blinded clinical trials of treatment resistant late life depression and only 14 small open label studies.
So any good study in this area would be welcome, but this study has also generated excitement because the positive result was quite clinically meaningful. Hence the accompanying editorial by Alan Thomas: “Management of late-life depression: a major leap forward.”
About half of older adults with a major depressive disorder do not achieve full remission with an initial trial of an antidepressant. Generally, the next step is a trial of a different antidepressant, or augmentation with another agent.
In this study, older adults who had not responded adequately received a trial of venlafaxine, titrated up to a maximum dose of 300 mg, and then those patients who did not respond fully to venlafaxine were randomized to receive either aripriprazole (initiated at 2 mg a day and titrated up to a target dose of 10 mg a day) or placebo.
There was a significant difference in outcomes. 40 (44%) of 91 participants randomly assigned to aripiprazole and 26 (29%) of 90 randomly 
assigned to placebo achieved remission. The difference became apparent early (as early as two weeks after starting aripiprazole) and lasted throughout the six months the study lasted (see figure at right).
A standard way of assessing whether a result is not just statistically significant, but is also clinically significant is the number needed to treat (NNT). The lower the NNT the more potent the intervention. In this study the number needed to treat (NNT) with aripiprazole of 6·6 (95% CI 3·5–81·8) is similar to the NNT in young adults of the two most well studied augmentation therapies: lithium (NNT=5) and atypical antipsychotics (NNT=9).
Another aspect of the study that has elicited positive comment is the careful attention to measuring potential adverse effects, since side effects of medications are more worrisome in older adults. Here also the study was reassuring.
“Of 46 possible side-effects queried, the most frequently reported with aripiprazole compared with placebo were increased dream activity (23 [27%] of 86 vs 12 [14%] of 87, weight gain 17 [20%] of 86 vs eight [9%] of 87), and tremor (five [6%] of 86 vs none of 87).
Akathisia was noted at some point during the randomised phase in more participants (n=13) assigned to aripiprazole than were assigned to placebo (p=0·02; table 3). Typically, akathisia was mild and did not persist to the end of the treatment phase…
Participants assigned to aripiprazole had a greater increase in bodyweight, but not in total body fat, than those assigned to placebo (figure 3). No differences were reported between groups in changes in percentage of body fat, or in total cholesterol, HDL, LDL, triglycerides, glucose, or insulin concentrations…”
References
Thomas AJ, Gallagher P, Robinson LJ, Porter RJ, Young AH, Ferrier IN, O’Brien JT. A comparison of neurocognitive impairment in younger and older adults with major depression. Psychol Med. 2009 May;39(5):725-33. doi: 10.1017/S0033291708004042. Epub 2008 Jul 30. PubMed PMID: 18667097.
Herrmann LL, Le Masurier M, Ebmeier KP. White matter hyperintensities in late life depression: a systematic review. J Neurol Neurosurg Psychiatry. 2008 Jun;79(6):619-24. Epub 2007 Aug 23. Review. PubMed PMID: 17717021.
Cooper C, Katona C, Lyketsos K, Blazer D, Brodaty H, Rabins P, de Mendonça Lima CA, Livingston G. A systematic review of treatments for refractory depression in older people. Am J Psychiatry. 2011 Jul;168(7):681-8. doi: 10.1176/appi.ajp.2011.10081165. Epub 2011 Mar 31. Review. PubMed PMID: 21454919.
Thomas A, O’Brien JT. Management of late-life depression: a major leap forward. Lancet. 2015 Sep 24. pii: S0140-6736(15)00304-9. doi: 10.1016/S0140-6736(15)00304-9. [Epub ahead of print] PubMed PMID: 26423179.
Lenze EJ, Mulsant BH, Blumberger DM, Karp JF, Newcomer JW, Anderson SJ, Dew MA, Butters MA, Stack JA, Begley AE, Reynolds CF 3rd. Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial. Lancet. 2015 Sep 24. pii: S0140-6736(15)00308-6. doi: 10.1016/S0140-6736(15)00308-6. [Epub ahead of print] PubMed PMID: 26423182.
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