Late-Life Treatment-Resistant Depression

Late-life depression (LLD) is prevalent and defined as major depressive disorder in adults 65 years and older. The prevalence rate of LLD among older adults living in the community is up to 5%.¹ LLD has deleterious effects and is associated with increased functional disability, cognitive impairment, all-cause mortality, and suicide.^2-5

LLD is characterized by its chronic course, with frequent relapses and recurrences.^6,7 The median time to a recurrent depressive episode tends to be short in LLD.^6,7 The unstable remission rate could be due to multiple factors, including increased previous depressive episodes, high anxiety levels, medical burden, or neurodegenerative illness. Furthermore, older adults with LLD tend to have a poor response to treatment with antidepressants, with the remission rates ranging between 55% and 81% in a first-line trial of selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs).^8-10

A subpopulation of older adults meet criteria for late-life treatment-resistant depression (LLTRD), defined as failure to respond to 2 or more adequate trials of antidepressant treatment.^11,12 LLTRD is challenging for practitioners as it tends to co-occur with cognitive impairment.¹³ Additionally, LLTRD is challenging to treat as older adults who have failed 2 previous antidepressant trials are less likely to achieve remission with a third SSRI/SNRI trial. The third-line treatment options in LLTRD are more complex to use than the SSRIs/SNRIs.¹⁴ These difficulties associated with LLTRD treatment can be exacerbating for clinicians and their patients and can lead to a sense of hopelessness and resistance to further treatments.¹⁵

Assessment of LLTRD

When facing LLTRD, it is imperative to consider several underlying causes that could be contributing to its presentation. It is essential to review the diagnosis, as the differential diagnosis of depression is broad and includes the following: major depressive disorder; a mood disorder due to a medical condition such as hypothyroidism; vitamin B₁₂ deficiency; sleep apnea; and substance-induced mood disorder, which can be seen in alcohol or opioid dependence.

Furthermore, it is critical to assess adherence to medication and treatment. Patients may not take their medications daily due to factors such as cognitive dysfunction, poor insight, ambivalence about treatment, worries about medication adverse effects, or the misleading concern that the medications have addictive properties. Adherence counseling may be needed for older adults who do not take their medications as prescribed.¹⁶ In mild degrees of cognitive impairment, having a family member or caregiver administering the medication also would be appropriate.

Several instruments can be used to assess depression severity in older adults with LLTRD, such as the Geriatric Depression Scale and the Beck Depression Inventory. Another standard tool is the Patient Health Questionnaire (PHQ-9), a self-administered measure consisting of 9 items and scores ranging between 0 and 27, with higher scores indicating higher severity of depression. Measurement-based care tends to be efficacious and treatment of depression in older adults is associated with a larger effect size than any single use of antidepressant.¹⁷ Thus, a PHQ-9 score of 10 or greater usually indicates that the depressive symptoms are severe enough to initiate a medication or treatment alteration.

Contributing Factors

There are several neurobiological factors that are associated with treatment resistance in LLTRD. LLD often co-occurs with medical comorbidities, and older adults with more significant medical burden often have lower response rates to treatment.^18,19 There is a bidirectional relationship between medical comorbidities and depression, and the interaction between these is complex.²⁰ For example, physical and functional impairment are significant risk factors for depression, whereas older adults with depression are at a higher risk of subsequent physical decline.²¹

In addition, cerebrovascular risk factors associated with coronary heart disease, diabetes, and vascular disease often contribute to LLD.²² Vascular disease promotes the development of LLD via white matter hyperintensities that tend to affect white matter pathways connected between the frontal cortex and the mood regulatory centers.²³ Furthermore, depressive symptoms’ persistence is associated with small basal ganglia and large cerebral cortical white matter lesions, whereas worsening depressive symptoms’ severity is associated with subcortical white matter lesions._^13,24,25

LLD is associated with cognitive deficits such as executive dysfunction, slowed information processing speed, inattention, and verbal fluency task difficulties.¹³ In particular, older adults with executive dysfunction were noted to have an increased risk of relapse and recurrence of LLD and a slow response to antidepressant treatment.¹³ White matter hyperintensities were found to be closely related to executive dysfunction and further predicted the chronicity of LLD.²⁶ Thus, there is a close relationship between executive dysfunction and the course of LLD, with both having related underlying mechanisms. Problem-solving therapy is effective in decreasing depressive symptoms and increasing treatment response and remission in older adults with LLD and executive dysfunction.²⁷ This could be of clinical value, and problem-solving therapy could be used with pharmacotherapy to treat LLD.²⁷

Anxiety symptoms co-occurring with LLD are notably associated with poorer rates of depression remission.²⁸ Older adults with LLD and more significant pretreatment anxiety usually take longer to respond to antidepressant treatment and have a higher recurrence rate.²⁸ Insomnia, which is found in more than 50% of adults older than 60 years, is an independent risk factor for LLD recurrence.²⁹ Thus, targeting insomnia in older adults through behavioral treatments such as cognitive behavioral therapy for insomnia and pharmacologic modalities can be considered as adjunctive treatment for LLTRD.

Some psychosocial factors, including loneliness, social isolation, and lack of social support, can be associated with LLD and may contribute to the persistence of depressive symptoms.³⁰ Living alone and decreased ability to participate in community activities tend to be factors associated with increased loneliness in older adults.³⁰

Management of LLTRD

Augmentation strategies, when a medication is added to an existing antidepressant, are typically used for older adults who have achieved a partial response with a primary antidepressant. Meanwhile, switching to an antidepressant from a different class is preferred when a patient with depressive symptoms does not respond or remit on the current antidepressant trial. The main goal of treatment is to achieve remission of depressive symptoms.

Several augmentation strategies exist, such as adding bupropion, lithium, or mirtazapine to the primary antidepressant. The selection of which augmenting agent to use depends on the patient’s clinical presentation and medication adverse effects. Additionally, augmentation with a low-dose antipsychotic such as aripiprazole, olanzapine, quetiapine, or brexpiprazole was shown to provide benefits and has been approved by the US Food and Drug Administration (FDA). Aripiprazole augmentation in older adults with LLTRD led to remission of depressive symptoms and was safe and well tolerated overall.³¹ The phase 4 Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) study (NCT02960763) exhibited that aripiprazole augmentation was significantly more efficacious and well tolerated than switching to monotherapy with bupropion in achieving depressive symptom remission in older adults with LLTRD.³²

Other augmentation strategies include adding memantine, an N-methyl-D-aspartate (NMDA) antagonist, in older adults with depression and subjective memory complaints.³³ Memantine significantly improved mood, anxiety, and cognitive function when added to escitalopram compared with placebo.³⁴ More recently, augmentation with intravenous ketamine, a novel antidepressant and NMDA antagonist, has been shown to improve depressive symptoms as well as executive functioning in older adults with LLTRD and was found to be safe and well tolerated overall.³⁵ Esketamine, the (S)-enantiomer of ketamine, was also efficacious for the augmentation treatment of depressive symptoms in older adults and its efficacy was comparable to what is seen in younger adults.³⁶

Noninvasive neuromodulation techniques are also safe and effective augmentation in older adults with LLTRD. Electroconvulsive therapy (ECT) is considered one of the most effective treatments for LLTRD, with reported response rate being 70% and remission rates of 60%.³⁷ Repetitive transcranial magnetic stimulation (rTMS) is also well tolerated and was shown to significantly decrease depressive symptoms in older adults.³⁸ Eliciting an electrical stimulus via a magnetic field, rTMS is used to stimulate the dorsolateral prefrontal cortex in depression. Additionally, rTMS offers specific advantages over ECT in older adults as it is not associated with the cognitive effects typically seen with ECT.³⁸

Concluding Thoughts

Multiple psychosocial and biological factors play a role in LLTRD. Given the complicated nature of LLTRD, a thorough evaluation of history and underlying causes of treatment resistance is important to ensure successful treatment plans for older adults.

Dr Oughli is an assistant clinical professor in the Department of Psychiatry and Biobehavioral Sciences at the University of California, Los Angeles. Dr Subramanian is a clinical instructor of psychiatry at Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. She is also psychiatry director of transcranial magnetic stimulation at Berenson-Allen Center of Non-Invasive Brain Stimulation, Beth Israel Deaconess Medical Center. Dr Lavretsky is a professor in residence in the Department of Psychiatry at the University of California, Los Angeles. She is president of the American Association for Geriatric Psychiatry, a distinguished fellow of the American Psychiatric Association and of the American Association for Geriatric Psychiatry, and a fellow of the American College of Neuropsychopharmacology. She is also on the Editorial Board of Psychiatric Times.

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