Optimizing the Treatment of Late-Life Depression

Late-life depression (LLD) is a major clinical and public health concern. The worldwide prevalence of major depressive disorder (MDD) in adults age 75 and older is 7.2% (1). With the number of older adults projected to increase from 962 million in 2017 to 2.08 billion in 2050, clinicians around the world should expect to care for many more older adults with depression (2). Depression affects quality of life and the ability to live independently, and it increases mortality (3). Up to 87% of older adults who die by suicide meet criteria for MDD (4), suggesting that effectively treating depression can save lives. Racial, ethnic, and sexual minority older adults face additional challenges. For example, racial minority older adults are less likely than White older adults to have their depression recognized, to receive prescriptions for antidepressants, and to receive specialty mental health care (5).

Clinicians can choose from among a number of evidence-based interventions for LLD, including psychotherapy, bright light therapy, exercise, antidepressants, transcranial magnetic stimulation, and electroconvulsive therapy (6). Antidepressants are modestly effective for LLD, with a response rate of 51% (7). People age 65 and older treated with antidepressants experience less suicidality than those given placebo (8). Older adults are at increased risk of antidepressant side effects, including falls, fractures, blood pressure changes, prolongation of the QT interval (with citalopram), SIADH/hyponatremia, and weight change. A systematic review and meta-analysis of antidepressant trials in older adults found an increased risk of adverse events with serotonin-norepinephrine reuptake inhibitors (SNRIs) relative to placebo, resulting in a number-needed-to-harm of 10 (9). The American Geriatrics Society Beers Criteria for potentially inappropriate medication use in older adults note that selective serotonin reuptake inhibitors (SSRIs), SNRIs, mirtazapine, and tricyclic antidepressants—that is, virtually all of the most commonly used antidepressants—are “drugs to be used with caution in older adults” (10). For older adults with mild to moderate depression, the U.S. VA/DoD Clinical Practice Guideline for the Management of Major Depressive Disorder recommends evidence-based psychotherapy (for example, cognitive-behavioral therapy or interpersonal psychotherapy) over antidepressants given such safety concerns; the authors aptly note that it is a misconception that older adults are not good candidates for psychotherapy (11).

Most older adults seek care for depression from their primary care providers. In fact, 12.3% of primary care visits by older adults in 2012 resulted in an antidepressant prescription (up from 9.9% in 2005) (12). SSRIs were most commonly prescribed (63.3%); tricyclic antidepressants and monoamine oxidase inhibitors were least commonly prescribed (13.1% total for the two drug classes) (12). Unfortunately, only 0.2% of primary care visits resulted in a referral to psychotherapy (12).

Antidepressants are associated with risks in older adults—but so is depression itself. Alternatives like evidence-based psychotherapy are often unavailable. This begs the question: In situations where the benefits of an antidepressant outweigh the risks, which antidepressant should a clinician choose?

Choosing the First Antidepressant

In this issue of the Journal, Ishtiak-Ahmed and colleagues (13) advance our understanding of how to select an antidepressant in previously untreated older adults with depression. The authors used data from two national registers in Denmark (one tracking all people born and living in Denmark since 1968 and the other tracking all prescriptions redeemed in pharmacies in Denmark since 1995) to identify patterns of older adults’ antidepressant use for the indication of depression. This group has previously reported a high rate of possible off-label use of antidepressants among older adults in Denmark (14); they also found that 73% of older adults in Denmark who received antidepressant prescriptions had polypharmacy (taking five or more medications), most commonly with other agents acting on the nervous system (89%) (15).

In this study, the authors associated the use of specific antidepressants with treatment outcomes: discontinuation, switching, augmentation, psychiatric care, suicide attempts, falls, cardiovascular events, and all-cause mortality. They included 96,737 older adults who took their first antidepressant for depression between 2006 and 2017. The authors limited the study to the 10 most commonly prescribed antidepressants in Denmark (in descending order): citalopram, mirtazapine, escitalopram, sertraline, mianserin (available in Europe, India, and Australia, but not in the United States or Canada), amitriptyline, venlafaxine, duloxetine, fluoxetine, and paroxetine. Sertraline was used as the reference against which other antidepressants were compared because Danish guidelines recommend it as the first-choice treatment for depression. Limitations of the study included the generalizability of the findings to countries outside Denmark and the inability to control for important confounders, such as the severity of depression and the use of alcohol and other substances, and not collecting data regarding the reason for discontinuation (the antidepressant may have been intolerable or ineffective or depression may have remitted, leading a person to choose, not unreasonably, to stop the antidepressant).

During 1 year of follow-up, 43.5% of subjects discontinued their initial antidepressant, 20.4% had their initial antidepressant augmented with a second agent (another antidepressant, lithium, or an antipsychotic), and 4.9% switched to another antidepressant. Overall, those who received prescriptions for sertraline seemed to fare best with respect to the selected outcomes, and those who received prescriptions for venlafaxine, mirtazapine, and escitalopram fared worst. The authors note that a previous study (16) using a different methodology—a systematic review and meta-analysis comparing antidepressants in adults of all ages—instead found that venlafaxine, mirtazapine, and escitalopram were more effective than other antidepressants in head-to-head trials. Surprisingly, Ishtiak-Ahmed et al. found that amitriptyline and paroxetine had better overall outcomes than all except sertraline and citalopram (13). I recommend avoiding amitriptyline and paroxetine in older adults because of their anticholinergic burden and, in the case of amitriptyline, the risk of orthostatic hypotension and cardiac effects. Ishtiak-Ahmed and colleagues ultimately agree with Danish prescribing guidelines that sertraline should be the first choice for treatment of LLD (13).

How does this compare with the existing guidance on selecting an antidepressant? Although not specific to older adults, the aforementioned VA/DoD guidelines state that clinicians should consider patient preference, the side effect profile of the medication, family history of response to antidepressants (i.e., when possible, select an antidepressant that family members have responded to), comorbid medical problems, currently prescribed medications, and cost (11). For patients who have previously been treated with antidepressants, history of prior response can guide treatment choice (11). Patients with current or past hyponatremia should be offered bupropion or mirtazapine, which are less likely than SSRIs and SNRIs to cause or exacerbate hyponatremia (17). For patients with dementia, citalopram has the strongest evidence base (albeit for agitation rather than depression) but is associated with QT interval prolongation (and carries an FDA black box warning about this) (18).

Pharmacogenetic testing raises the possibility of precision medicine in LLD. A systematic review of pharmacogenetic studies of antidepressant response, plasma levels, and tolerability in people age 50 and older found that slow metabolizers at CYP 2D6 had higher plasma levels of relevant antidepressants and required lower doses than normal metabolizers (19). People with the L/L genotype of SLC6A4 5-HTTLPR may be more likely to respond to antidepressants than carriers of an S allele (19). The largest prospective study to date of pharmacogenetics in older adults (N=206) found no difference in depression severity, the primary outcome measure, at 8 weeks in those receiving pharmacogenetics-guided care compared with treatment as usual, although there were statistically significant differences in response rate (29.6% vs. 16.1%) and remission rate (20.1% vs. 7.4%) (20). While these data are promising, additional studies are needed, especially with respect to the cost-effectiveness of pharmacogenetics.

Improving the Care of Older Adults With Depression

So, where does this leave us? First, primary care providers should screen all their patients who are age 65 and older for depression (21). Although the U.S. Preventive Services Task Force recommendations are silent regarding which instrument to use and how often to use it, I recommend using the PHQ-9 annually. Patients who screen positive (e.g., a PHQ-9 score ≥5) should undergo further evaluation to establish the diagnosis, to evaluate the risk of suicide, and to address medical and substance-related issues that could be causing depression, for example, hypothyroidism, obstructive sleep apnea, dementia, alcohol or cannabis use, or medication side effects. Bipolar disorder should be screened for, since the treatment of bipolar depression is very different from the treatment of MDD.

Older adults who are found to have mild to moderate MDD (a PHQ-9 score of 5–14) should be offered evidence-based psychotherapy, namely, cognitive-behavioral therapy, interpersonal psychotherapy, problem-solving therapy, or mindfulness-based cognitive therapy (6). Patients with LLD may also benefit from exercise and bright light therapy (22, 23). Patients and their families should be informed of resources like the 988 Suicide and Crisis Lifeline (in the United States).

Clinicians should consider prescribing an antidepressant to older adults with moderate to severe depression (a PHQ-9 score ≥10), carefully weighing risks (falls, hyponatremia, etc.), benefits, and drug-drug and drug-disease interactions. The first antidepressant should probably be sertraline or escitalopram, since these have been extensively studied in older adults, are generally well tolerated, and are unlikely to result in drug-drug interactions (24). Clinicians should educate patients about taking the antidepressant daily and for an adequate duration and about reporting any side effects. Clinicians should start low, go slow, but go—that is, titrate the medication to an effective dose—all the while being attentive to side effects and monitoring treatment outcome.

Many older adults will not tolerate or benefit adequately from the first antidepressant they take. In fact, 11% of Medicare beneficiaries with MDD have failed to respond to two or more antidepressant trials of adequate dose and duration (25). Reasonable next steps include switching to another antidepressant, combining antidepressants (e.g., an SSRI and bupropion), and augmenting with aripiprazole, lithium, or methylphenidate (6). The OPTIMUM study compared five interventions in people age 60 and older with MDD who had not responded to two or more antidepressant trials (26). Adding aripiprazole (starting at 2.5 mg/day, maximum of 15 mg/day) or adding bupropion (starting at 150 mg/day, target dosage of 300 mg/day, maximum dosage of 450 mg/day) to the current antidepressant was most effective (remission rates of 28.9% and 28.2%, respectively). Surprisingly, aripiprazole was better tolerated than bupropion, with subjects having fewer falls. Switching to bupropion, adding lithium, and switching to nortriptyline were less effective strategies (remission rates of 19.3%, 18.9%, and 21.5%, respectively). We have a long way to go in developing the evidence base for a fully fleshed out algorithm for treatment-resistant LLD, including the role of ketamine and esketamine.

Older adults with severe depression, bipolar depression, or an elevated risk of suicide should be referred to a psychiatrist and may benefit from psychiatric hospitalization and/or electroconvulsive therapy. Primary care clinics, federally qualified health centers, and rural health clinics that have not yet done so should consider implementing the collaborative care model, which reduces depression and suicidality in older adults (27, 28).

Changes in public policy and the funding of mental health services will be needed to address the growing number of older adults with depression. Fewer and fewer U.S. psychiatrists—now down to 55%—accept Medicare, the health care insurance that the vast majority of older Americans have (29). Medicare’s low reimbursement rates and high administrative burden may affect psychiatrists’ participation in Medicare and may also decrease the number of physicians interested in primary care or geriatrics (30). Black and Hispanic Medicare beneficiaries have worse depression outcomes than their White counterparts (31). Older adults who live in rural areas or who reside in long-term care facilities have especially poor access to psychiatrists (29, 32). Improving depression outcomes in older adults will require addressing these health care disparities.

The U.S. Centers for Medicare and Medicaid Services (CMS) has recently taken steps to improve access to mental health services for older adults. As of January 2024, CMS will allow marriage and family therapists, mental health counselors, and addiction counselors who also qualify as mental health counselors to enroll in Medicare, potentially expanding the mental health workforce for older adults by up to 400,000 therapists (33). CMS will also cover intensive outpatient services, which could provide depressed older adults an additional level of care between hospitalization and routine outpatient care (33). CMS has acknowledged “that there is a systemic undervaluation of work estimates for behavioral health services” that “could serve as an economic deterrent to furnishing these kinds of services and be a contributing factor to the workforce shortage” (34) but for 2024 has proposed only limited increases in reimbursement for mental health services (33) and no reduction of administrative burden. Congress will have to act to make more substantial changes.

Ishtiak-Ahmed and colleagues highlight the importance of careful selection of the first antidepressant for LLD (13). In addition, we need to make clinical and public policy changes that ensure that all older adults with depression are identified, correctly diagnosed, and offered evidence-based treatment.