Old Before Their Time: Aging and Treatment Resistant Depression

The consequences of ineffective or only partially effective treatment for depression in older adults are profound. Depression in older adults typically follows a chronic and recurring course, is a leading cause of disability and premature mortality, and is one of the most important risk factors for cognitive decline, dementia and suicide. “Unfortunately, Treatment-Resistant Depression (TRD) is the norm rather than the exception in older adults with depression, as most fail to remit with standard antidepressant pharmacotherapy,” says Dr. Steven Roose, Professor of Clinical Psychiatry at Columbia University Vagelos College of Physicians and Surgeons and the New York State Psychiatric Institute (NYSPI).

TRD leads to excess health care utilization, high caregiver burden, and poorer outcomes for many co-occurring illnesses, including diabetes and cardiovascular disease. The impact of TRD will rapidly grow as the US and world populations age. Yet, despite the high stakes for public health, the comparative risk/benefit ratio of antidepressant use by older adults with TRD remains unstudied. This stands in contrast with numerous studies of younger adults, including STAR*D and VAST.

To address this staggering clinical problem, the Patient-Centered Outcomes Research Institute (PCORI) has funded a five-center, 1500-patient $12 million-dollar study for “Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM).” This study is the largest ever done on late-life depression. Dr. Roose serves as lead investigator at OPTIMUM’s New York site, located at NYSPI/Columbia, and is joined by his colleagues at Washington University in St Louis, Pittsburgh, UCLA and Toronto. There are unique safety concerns about the use of antidepressants in older adults: cardiovascular risks, cognitive decline, falls and fall-related injuries, and even death. Understanding the risks and benefits of antidepressant strategies in older adults could vastly improve the quality of life of seniors, and could save billions of dollars each year in health care costs.

The primary goal of OPTIMUM is to compare the effectiveness of augmentation and switch strategies for treatment-resistant depression in older adults. The investigators also plan to examine factors that may moderate clinical response in TRD in older adults including age, gender, and other medical conditions. They will investigate whether increased vascular burden and specific types of cognitive functioning, including episodic memory or executive function, are connected to a poorer response to the treatment strategies used in OPTIMUM.

OPTIMUM uses a Sequential, Multi-Assignment, Randomized Trial (SM AR T) design to test first- and second-line treatments with clinicians moving from the simplest to the more challenging management strategies. For depressed patients over 60 who have failed at least 2 adequate trials (in dose and duration) of antidepressant pharmacotherapy, Step 1 of the study will determine the benefits and risks of first-line strategies (“simpler to use, fewer risks”). These include aripiprazole or buproprion augmentation of antidepressants or switching to buproprion. Step 2 of the study will determine the benefits and risks of second-line strategies (“requires more monitoring”), including lithium augmentation or switching medications to nortriptyline. Patients who complete the acute trials will continue their treatment for 12 months. The focus on sustained response is particularly critical given that late-life depression has a high relapse rate. Furthermore, as antidepressants are often prescribed for extended periods to prevent recurrence, it is essential to determine the long-term risks of chronic antidepressant use in the more vulnerable elderly population. “The OPTIMUM study will provide much-needed evidence to guide treatment for this high-risk population,” says Dr. Roose.

The OPTIMUM study is innovative in its efforts to ensure that the patient’s PCP or clinic psychiatrist acts as the treating doctor, with the research psychiatrists serving as consultants. The study team works with the treating physician to prescribe the optimal medication and to implement a measurement-guided treatment plan. Alternatively, providers can refer patients for direct treatment at the Clinic for Aging, Anxiety, and Mood Disorders (CAAM), where their care is managed by Dr. Roose. To date, most patients have been referred by their PCP to CAAM for treatment due to unfamiliarity and concerns about prescribing aripiprazole, nortriptyline or lithium. By providing treatment provider options, OPTIMUM remains flexible in meeting the needs of both the patient and the treating physician so that as many people as possible can benefit from this level of much-needed care.

In collaboration with the New-York-Presbyterian Ambulatory Care Network and the Associates in Internal Medicine, the NYC OPTIMUM site has focused on engaging the diverse Washington Heights and Harlem communities. Minorities experience depression at rates similar to those of their white counterparts but are less likely to be offered evidence-based care or access to a mental health specialist. The bilingual staff at CAAM and NYC OPTIMUM are working to bridge this gap by offering all study procedures in both English and Spanish. The staff collaborates with the PCPs, psychiatrists, and social workers who serve the Washington Heights community to bring this innovative and pragmatic study to those in the community who need it most. The staff at CAAM and NYC OPTIMUM are also working with neighborhood senior centers and adult living communities to ensure that those community-dwelling older adults have access to the type of mental health care that they need but too often do not receive.

Older adults with TRD are a heterogenous group. Research is required to deconstruct this heterogeneity to better understand clinical trajectories and to develop the best treatment options. One focus is on the relationship between TRD and cognition in later life. As Dr. Patrick Brown, Director of the CAAM and Co-Investigator of OPTIMUM, notes, “Depression in later life, and in particular TRD in later life, is associated with increased risk of cognitive decline and progression to dementia.” In a companion study to OPTIMUM, the National Institute of Mental Health has funded the $13-million OPTIMUM NEURO study. Using neuroimaging and cognitive testing, Dr. Brown and his colleagues from Washington University in St Louis, Pittsburgh, UCLA and Toronto will evaluate the trajectories of cognitive function in patients being treated in OPTIMUM over 2 years. The goal of OPTIMUM NEURO is to test whether non-remitting depression in patients treated in the OPTIMUM study is associated with greater cognitive deterioration. Additionally, given the design of the study and the methods used, the investigators in OPTIMUM NEURO will be able to evaluate the neural circuitry connected to greater cognitive decline in these study participants.

The OPTIMUM and OPTIMUM NEURO studies are but two examples of the innovative work being done in the Neurobiology and Therapeutics of Aging Division (NTAD) within the Psychiatry Department at Columbia University and the New York State Psychiatric Institute. The division’s Director, Dr. Bret Rutherford, describes the central premise of NTAD: “This newly formed research division is focused on the premise that the phenomenology, pathophysiology, and long-term trajectory of a given psychiatric disorder may significantly differ when the disorder occurs in an older adult compared to a younger adult.” Aging-associated processes may cause, worsen, or influence the treatment responsivity of neuropsychiatric disorders.

NTAD investigators, such as Drs. Roose, Rutherford, and Brown, seek to understand the complex interplay between aging-related processes and the pathophysiology underlying psychiatric disorders by studying (1) the etiology and pathophysiology of late life mental disorders; (2) the relationships between physiologic processes associated with aging and the development of late-life neuropsychiatric disorders; and (3) the prevention and treatment of late-life disorders using novel pharmacologic, somatic, or psychotherapeutic treatments. Of particular interest to the investigators at NTAD are aging-related processes with protective effects on the structure and function of physiological systems including the brain, processes which promote healthy aging across the lifespan. Ongoing studies in NTAD include work focused on targeting dopamine to improve cognitive and motor speed and depression in later life; treating hearing impairment as a way of improving depression outcomes in older individuals; examining the intersection between fatigue and late-life neuropsychiatric disorders; and understanding the interrelationship between the biological syndrome of frailty and depression.

“At the end of the day, psychiatry has done a disservice to older adults who suffer from disorders like depression. All of our diagnostic and pathophysiological models of psychiatric illness are based on studies of younger individuals, and have ignored the role that aging processes play in the onset and treatment of these disorders. By trying to understand these aging processes through our work in NTAD and on the OPTIMUM and OPTIMUM NEURO studies, our long-term hope is to not just get our older patients better, but to fundamentally improve their health trajectories for years to come,” Dr. Brown summarizes.

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Treatment-Resistant Depression