patient care perspectives

Finding Answers for Older Patients With Major Depressive Disorder

by Charles F. Reynolds, III, MD

Overview

For older patients who may be faced with chronic illness, depression, and cognitive decline, current studies may yield important answers. Late-life depression can be stubborn. It can also be complicated by comorbid illness and the cumulative burden of various neurodegenerative processes that have been exerting their influences over a lifetime. While augmentation therapy is effective for a large proportion of older adults with treatment-resistant depression, many people in this category do not reach remission. Advances in care will likely emerge from distinct lines of research. Two areas of interest presently are the optimization of existing therapeutic strategies and the role of depression prevention.

Expert Commentary

Charles F. Reynolds, III, MD

Distinguished Professor of Psychiatry Emeritus
University of Pittsburgh
School of Medicine
Pittsburgh, PA

“What we don’t know, in my opinion, is whether a strategy like augmentation of venlafaxine with aripiprazole is better than switching to another agent.” 

Charles F. Reynolds, III, MD

Optimizing Therapy for Older Patients With Treatment-Resistant Depression

Treatment-resistant depression is a common problem among individuals aged 60 years and older. Regarding switching vs using various augmentation strategies, the best course of action is not always clear. Several years ago, we published findings from a fairly large, placebo-controlled study ago in The Lancet, demonstrating that aripiprazole augmentation of venlafaxine maintenance therapy handily beat placebo augmentation in the patients aged 60 years and older. The expected associated mild degrees of akathisia and parkinsonism were evident, so it can be a double-edged sword. Nevertheless, the advantages of the active augmentation agent were apparent. What we don’t know, in my opinion, is whether such a strategy, ie, augmentation of venlafaxine with aripiprazole, is better than switching to another agent,  such as one of the newer serotonergic agents.

 

The OPTIMUM Study Is Enrolling Older Patients With Treatment-Resistant Depression

It will be the goal of the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) study to determine the benefits and risks of switching vs augmentation strategies in this population. OPTIMUM is a 5-site study (Washington University, UCLA, Toronto, Columbia, and Pittsburgh) that aims to enroll 1500 older adults with treatment-resistant depression. The Patient-Centered Outcomes Research Institute (PCORI) recently funded this endeavor.

Treatment resistance is defined as a failure to respond adequately to 2 or more antidepressant treatment trials of recommended dose and length (at least 12 weeks), whereby inadequate response is characterized by a Patient Health Questionnaire-9 (PHQ-9) score of 6 or higher. The treatment arms are shown in the table.

 

MDD_TreatmentArms

 

Exploring Unmet Needs in Real-World Settings

We have a second step in the OPTIMUM treatment algorithm for patients whose depression is not relieved at the end of 10 weeks. We had seen in previous trials with various augmentation strategies that over half of the people were still not achieving remission. In developing the treatment resistance algorithm in OPTIMUM, we tried to be mindful of the real world of primary care and psychiatric practice. Thus, the patients who have not done well in the step 1 will be offered the chance to be switched to a therapeutic trial of nortriptyline or an augmentation with lithium carbonate (sometimes known as oldies but goldies), old-fashioned agents that do have some track record of helping people with difficult-to-treat depression. Primary outcomes will be psychological well-being and remission from depression as well as serious adverse events. 

An interesting side note related to lithium, but not the OPTIMUM study per se, is the question of neuroprotection. My colleague at Pittsburgh, Ariel Gildengers, MD, will be looking at the effects of lithium on mild cognitive impairment (in people without bipolar disorder) to see if its use is associated with slowing of cognitive progression. There are some interesting data on white matter disease, and his data suggest that longer-term exposure to lithium is associated with a decreased burden of white matter disease in people living with bipolar disorder. It’s been hard for him to show a correlation with actual neurocognitive performance, but to me it’s an interesting notion that lithium might be protective against the brain-toxic effects of bipolar disease.

Another relevant development to watch unfold is the personalization of treatment by identifying moderators of treatment response. My group showed that preservation of set-shifting capacity, but not response inhibition, identified older depressed patients who respond to augmentation of venlafaxine with aripiprazole. Set-shifting performance indicates which older adults with treatment-resistant depression may respond favorably to augmentation with aripiprazole and thus may help to personalize treatment.

Targeting Late-Life Depression in View of Dementia Risks

Prevention is another approach that interests me. Many older individuals with MDD are faced with significant comorbidity, declining cognitive function, and essentially few good treatment options that will deliver marked improvement in the areas that are most important to them. While important work on new molecular entities continues, it will also be important to develop preventive strategies that may be effective for the parts of the population iceberg that that are submerged (ie, older people at risk for late-life depression and cognitive decline).

Overlapping risk architecture between depression and dementia is an interesting area. Late-life depression is associated with an increased risk for all-cause dementia, vascular dementia, and Alzheimer’s disease. The question of whether the prevention of late-life depression might also afford some protection against these and other dementing illnesses is an interesting one to me.

Presently, I am conducting prevention research with colleagues in India. I have an interventional development grant from the National Institutes of Health, and we are trying to develop scalable models of depression prevention for older adults at risk, particularly in primary care. Such models might have some utility because they use lay-health counselors in low- and middle-income countries. We are carrying out this work in Goa, India.

“While important work on new molecular entities continues, it will also be important to develop preventive strategies that may be effective for the parts of the population iceberg that that are submerged (ie, older people at risk for late-life depression and cognitive decline).”

Charles F. Reynolds, III, MD

Interestingly, the model that we are using involves the principles of problem-solving therapy, a learning-based approach to psychotherapy that does seem to have some positive cognitive effects, as well as depression prevention effects. Many people would consider problem-solving therapy, a derivative of cognitive behavioral therapy, as an activating intervention.

References

Cohen A, Dias A, Azariah F, Reynolds CF, et al. Aging and well-being in Goa, India: a qualitative study. Aging Ment Health. 2016 Sep 30:1-7. doi: 10.1080/13607863.2016.1236239.

Diniz B, Butters MA, Albert SM, Dew MA, Reynolds CF, III. Late-life depression and risk of vascular dementia and Alzheimer’s disease: a systematic review and meta-analysis of population-based cohort studies. Br J Psychiatry. 2013;202(5):329-335.

Kaneriya SH, Robbins-Welty GA, Smagula SF, et al. Predictors and moderators of remission with aripiprazole augmentation in treatment-resistant late-life depression. JAMA Psychiatry. 2016;73(4):329-336.

Lenze EJ, Mulsant BH, Blumberger DM, et al. Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomized placebo-controlled trial. Lancet (London, England). 2015;386(10011):2404-2412.

Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) study. https://clinicaltrials.gov/ct2/show/NCT02960763?term=optimum+depression&rank=1. Accessed on June 5, 2017.

Reynolds CF, Thomas SB, Morse JQ, et al. Early intervention to preempt major depression in older black and white adults. Psychiatr Serv. 2014;65(6):765-773.

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