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Assessment and treatment of major depression in older adults
Handbook of Clinical Neurology, Vol. 167 (3rd series) Geriatric Neurology S.T. DeKosky and S. Asthana, Editors https://doi.org/10.1016/B978-0-12-804766-8.00023-6 Copyright © 2019 Elsevier B.V. All rights reserved
Chapter 23
Assessment and treatment of major depression in older adults CHARLES F. REYNOLDS III1*, ERIC LENZE2, AND BENOIT H. MULSANT3 1 University of Pittsburgh School of Medicine, Pittsburgh, PA, United States 2 3
Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
Abstract Late life depression is a significant public health problem as well as a burden on patients, their families, and caregivers. There are significant associations of late life depression with medical disorders and cognitive impairment, the latter due to effects of the depression itself or association with dementia. Diagnostic criteria and screening tests have continued to evolve and provide structure and guidelines for assessment. Accurate diagnosis and treatment are of utmost importance to improve quality of life, alleviate suffering, and prevent suicide. A number of effective antidepressant medications are available; combination therapy with these medications and cognitive behavioral therapy appear most efficacious, and maintenance therapy can decrease the chances of remission. A sequence for treatment of late life depression is provided, with strategies for treatment-resistant depression. The relationship of dementia to depression and the interaction of depression with mechanisms of aging are major foci of research.
This chapter begins with a review of the public health of and clinical significance of depression in older adults. Depression is a risk factor for both Alzheimer’s disease (AD) and vascular dementia. It imposes multiple burdens upon its victims and their family care givers, amplifying the disabilities of medical comorbidities and neurologic illness. The clinical signature of depression in later life is its coexistence with medical illness, resulting in an amplification of disability and suffering, foreshortening of life expectancy, and worsening of caregiver burden. Cognitive impairments are also a core feature of clinical depression in older adults, reflecting the toxic effects of depression on brain health. Here we consider the differential diagnosis of depression in later life, including a variety of approaches that are in use in general medical and neurologic practice. The major risk is underdiagnosis and attendant failure to provide adequate treatment. We also review evidence-based approaches to treatment, together with the limitations of the evidence, and we underscore the importance of taking a long-term view of treatment. Getting well is important but not enough; it is staying well that counts because depression in older adults is often a chronic, relapsing illness.
CLINICAL AND PUBLIC HEALTH PERSPECTIVE ON MAJOR DEPRESSION IN LATER LIFE The public health burden of depression in older adults is reflected in suffering and disability (particularly depression’s amplification of disability associated with concurrent medical and neurologic disorders), increased caregiving burden for family members, greater utilization of healthcare resources (as a result of depression not being recognized or adequately treated), increased risk of all-cause mortality and of suicide, and increased risk of AD and vascular dementia. At the same time, advances in intervention science have demonstrated that major depression in older adults can be treated to remission and that remission can be sustained with appropriate maintenance treatment. The latter point deserves emphasis because depression in older adults often follows a relapsing, chronic course unless adequately treated acutely and long term. Factors contributing to a chronic relapsing course are, variously, psychosocial in nature (e.g., bereavement, social role changes, social isolation),
*Correspondence to: Charles F. Reynolds III, MD, 758 Bellefield Towers, 3811 O’Hara Street, Pittsburgh, PA, 15213, United States. Tel: +1-412-246-6440, E-mail: [email protected]
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sleep- and pain-related, secondary to cerebrovascular disease and neurodegenerative disorders, reflective of limited access to adequate treatment, increasing functional disability, and finally, possibly a manifestation, or cause, of accelerated cognitive aging as well as cellular and molecular aging (e.g., accelerated telomere attrition).
CLINICAL PRESENTATION AND DIAGNOSIS The differential diagnosis of depression in older adults (aged 60 and older) encompasses major depressive disorder (MDD), bipolar disorder, minor depression, bereavement (including prolonged or complicated grief ), adjustment disorder, mood disorders related to a general medical condition, substance-induced mood disorder, and dementia with depressed mood. This differential diagnosis highlights the signatures of major depression in older adults, namely, its concurrence with medical comorbidity and cognitive impairment. Major depression in older adults usually does not present “in pure culture,” but rather with concurrent medical, neurologic, and psychosocial issues. The core features of a major depressive episode in DSM-5 (Diagnostic and Statistical Manual, Fifth edition, of the American Psychiatric Association) include depressed mood or loss of pleasure (anhedonia), together with at least four other symptoms: loss (or increase) of appetite or weight; insomnia or hypersomnia; psychomotor agitation or retardation (observable by others); fatigue or loss of energy; worthlessness or guilt; diminished ability to think, concentrate, or make decisions; and recurrent thoughts of death, passive or active suicidal ideation. Depressed mood and anhedonia are the two core symptoms, and when both are absent, a definitive diagnosis cannot be made. Symptoms must be present for 2 weeks or longer, nearly every day, and most of the day, and they must be of such severity as to be distressing or to interfere with functioning. Two screening questions for depression are based on the Patient Health Questionnaire-2 (PHQ-2): how often has the patient been bothered over the past 2 weeks by either (1) little interest or pleasure in doing things; or (2) feeling down, depressed, or hopeless (Spitzer et al., 1999). When a patient presents with depressive symptoms or a clinical meaningful depression is suspected, Step 1 of a diagnostic algorithm is to assess whether the patient meets criteria for a major depressive episode. Step 2 encompasses an assessment of medical and psychosocial context: including substance misuse, general medical condition co-occurring with depression, vascular or Alzheimer’s dementia, death of a loved one (or other recent stressors), and past history or recurrent major depressive or bipolar disorder episodes. Step 3, in the absence of a major depressive episode, but with distress or impairment, could assess an adjustment disorder or minor depression. In DSM 5 the bereavement exclusion has
been dropped, suggesting that a major depressive episode can be diagnosed within the first 2 months after bereavement if diagnostic criteria are met. In DSM-IV, a major depressive episode was not diagnosable until 2 months after the loss, in recognition of the overlap between acute grief and depression, in order to avoid pathologizing (medicalizing) normal grief. In DSM 5 depression is diagnosable at any point after the loss if diagnostic criteria are met. In other words, the DSM 5 Task Force concluded that bereavement does not “immunize” against depression. “Persistent complex bereavement disorder” (also known as “complicated grief”) is listed in Section III of DSM 5 as a condition for further study. As of now, there is no consensus about the best diagnostic criteria. [Readers interested in this topic are referred to Katherine Shear’s clinical review in the New England Journal of Medicine (Shear, 2015).] Challenges in interpreting diagnostic features of depression in older adults arise because of overlaps in clinical presentation. For example, loss of pleasure (anhedonia) should be distinguished from the apathy of dementia or other neurologic conditions. Loss of appetite or weight can also be seen in concurrent physical illness or with dementia. Sleep disturbances, such as insomnia, also occur with chronic pain and with many physical illnesses, including breathing-related sleep disorders such as obstructive sleep apnea (which should be considered in the differential diagnosis of depression in older adults with sleep disturbances). Psychomotor retardation can be characteristic of neurologic illnesses, similar to the inability to think, concentrate, or to make decisions. Worthlessness and thoughts of death occur at the end of life, with terminal illness. Depression as a manifestation of physical or neurologic illness is common in such conditions as Parkinson’s disease (PD); in the wake of cerebrovascular disease (e.g., stroke); with metabolic conditions (e.g., vitamin B12 deficiency), endocrine conditions (e.g., thyroid and adrenal diseases), autoimmune conditions (e.g., lupus), in viral and other infections (e.g., hepatitis, HIV), and in certain cancers (e.g., pancreas) or with space-occupying lesions. The complexity of clinical phenotypes has generated several approaches to diagnosing depression in the context of concurrent medical and neurologic disease: (1) the exclusive approach does not consider neurovegetative symptoms in the diagnosis; for instance, in a patient with cancer, changes in sleep, energy, appetite, or weight would not be considered when making a diagnosing depression; (2) the substitutive approach replaces neurovegetative symptoms with other or additional cognitive symptoms; for instance, a neurovegetative symptom like weight loss is not considered when diagnosing a depression, but both feelings of guilt and worthlessness can be counted towards the five symptoms required to diagnose a major depressive episode; (3) the etiologic approach evaluates each symptom separately as to pathogenesis;
ASSESSMENT AND TREATMENT OF MAJOR DEPRESSION IN OLDER ADULTS for instance, in a cancer patient, the clinician makes a clinical judgment on whether a specific neurovegetative symptom (eg., weight loss) is caused by the cancer or whether it should be attributed to a depressive disorder; and finally, (4) the inclusive approach counts all depressive symptoms as present, regardless of their potential (and multiple) causes (Mulsant and Ganguli, 1999). The inclusive approach maximizes sensitivity and may be most useful clinically with respect to recognizing depression and implementing treatment, together with interventions for concurrent medical and neurologic disorders. Our opinion is that concurrent intervention for both depression and concurrent medical disorders puts the odds in the patient's favor toward optimal health related quality of life. Several features help to distinguish depression in older adults. In late life, depression amplifies disability and suffering, exacerbates physical symptoms such as pain, worsens cognitive impairment, drives utilization of healthcare resources, and increases risk for early medical mortality and for suicide. The most specific signatures of depression in older adults include the medical and psychosocial context in which it occurs: cognitive impairment, age of onset, concurrent physical and neurologic illnesses, and psychotic features. Because of the phenotypic complexity, detection of depression in primary care remains a challenge, in part because other medical conditions cloud the diagnosis, and because older people are more likely to present with pain and other somatic symptoms. They are also less likely to use the word “depressed” and instead may complain of poor sleep, worrying, and not enjoying or seeing the point of life. After controlling for presenting symptoms, according to the National Ambulatory Medical Care Survey (NAMCS), depression is 56% less likely to be diagnosed in older patients, 37% less likely to be diagnosed in African-Americans, and 35% less likely in Medicaid patients (Harman et al., 2001). The main reasons that a diagnosis of depression may be missed in an older primary care patient are, first, that the older adult does not report or denies depressed mood, but rather may focus on somatic symptoms. Also, the clinician may choose to focus on seemingly more urgent physical problems that compete for attention. The clinician may discount depressive symptoms because they make sense in the psychosocial context of the patient’s life or because they may seem to be attributable to a somatic illness. S/he may further be concerned about not offending the patient or family by using a stigmatized, and stigmatizing, word (depression). To avoid an “I am not depressed” response and barrier to treatment, it is helpful to use words from the patient’s own speech (“worrying,” “not sleeping,” “stressed,” etc.) and, almost always, to seek the perspectives of family caregivers and gain their assistance with treatment initiation and adherence.
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In this context of strategies to enhance recognition, the clinician may find it useful to detect the following clues in an ambulatory patient: (1) help-seeking, with persistent complaints of pain, fatigue, and insomnia as well as multiple diffuse symptoms; and (2) frequent calls and visits to the physician (high utilization of services). Additional clues in hospitalized patients include a recent history of coronary artery bypass surgery, myocardial infarction, stroke, or hip fracture; delayed recovery, treatment refusal, and discharge refusal. Among nursing home residents, additional clues to depression include apathy, withdrawal and isolation, failure to thrive, agitation, delayed rehabilitation, increasing dependency, and refusal to eat or drink (considered as a form of passive suicidal behavior). Blood tests that can be useful when assessing an older person with a depressive syndrome include the following: (1) TSH (hypothyroidism), (2) B12 and folate levels, (3) complete blood count with differential, (4) sodium (hyponatremia), (5) liver function tests (indirect evidence of alcohol use disorder), (6) fasting blood glucose, (7) serum creatinine, (8) serum albumin (to assess nutritional status), and (9) parathyroid hormone and vitamin D levels.
LINKS BETWEEN DEPRESSION AND DEMENTIA There are several links, or pathways, interconnecting depressive symptoms and dementia. Depression is now recognized as a risk factor for dementia, as well as a prodromal expression of dementia and as a presenting symptom of dementia (Diniz et al., 2013). There is a bidirectional relationship between cognitive impairment and depression in later life, such that depressive symptoms and clinical depression are common in patients with dementia; and, conversely, cognitive impairment and dementia are common in patients with clinical depression. In the older population generally, the crosssectional prevalence of clinical depression is about 4%, but it is substantially higher in persons with neurologic illness, with conservative estimates of 20% in AD and in stroke, 40% in Huntington’s disease, and 50% in PD. Helpful distinguishing features in AD include apathy and agitation, sundowning, weight loss without loss of appetite, a tendency to minimize or deny cognitive impairment despite the presence of impaired memory and executive dysfunction, and aphasia and apraxia. In contrast, the hallmarks of depression in older adults are anhedonia and anxiety, sleep disturbance, appetitive disturbance with weight loss, and subjective complaints of cognitive impairment with frequent “I don’t know” responses, in the presence of intake motor and language skills (Butters et al., 2004). Cognitive impairments in older depressed patients are nonetheless common and
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broad-based, in particular slowing of information processing speed and decrements in visuospatial ability, episodic memory, and executive functioning.
POSSIBLE ETIOLOGIC PATHWAYS LINKING COGNITIVE DISORDERS AND DEPRESSION IN LATER LIFE Depression may be an early psychologic reaction to subclinical cognitive decline, thus representing a grief reaction to the loss of the self. Depression may also cause cognitive impairment and lower the threshold for the diagnosis of dementia. Cerebrovascular pathology may lead to both “vascular depression” (see following text) and to vascular dementia. Loss of noradrenergic neurons due to AD pathology may manifest as prodromal depression at the onset of dementia. Depression appearing for the first time in later life (late-onset) is frequently accompanied by a lower likelihood of a family history and may in fact be a prodromal expression of AD or as a manifestation of cerebrovascular disease (termed “vascular depression”). Late-onset depression also occurs in the context of other medical and psychosocial issues, such as those that accompany the end of life. Pathways to depression may involve disruption of neurotransmitters or of neural circuits (e.g., as in stroke, Parkinson’s, or Alzheimer’s), physiologic stress (e.g., post coronary artery bypass graft (CABG) or post-MI), as a consequence of functional disability (following hip fracture or renal failure), or in the wake of psychosocial stresses (such as attachment bereavement or transitions in major social roles, such as retirement). Depression in older adults is often multifactorial. Possible pathways include monoamine deficiencies, circadian rhythm disruption, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, inflammation (pro-inflammatory cytokines, which stimulate the HPA axis and monoamine activity in the brain), and vascular insufficiency with hypoperfusion. Vascular disease may predispose, precipitate, or perpetuate the symptoms and signs of late-life depression, including cognitive deficits, psychomotor retardation, lack of insight, and disability out of proportion to the severity of the depression. White matter lesions, seen on magnetic resonance imaging as white matter hyperintensities, are characteristic of the construct of “vascular depression” and of its clinical expression as a depression–executive dysfunction syndrome (Agudelo et al., 2015).
SUICIDE IN LATE-LIFE DEPRESSION Suicide in later life is one of depression’s most tragic consequences, not only for the victim, but also for family members and other “informal” care givers. It is a
reminder that depression can be a lethal illness. Suicidal ideation can be active or passive, e.g., refusing treatment. Older adults, especially white males, have some of the highest suicide rates in North America, with higher intent and likelihood of completion by the use of violent methods (e.g., hanging, firearms) being more common than nonviolent methods (Szanto et al., 2002). Four clinically useful screening questions address whether the patient (1) cares if s/he lives or dies, (2) wants to die now, (3) thinks that reasons for staying alive are better than the reasons for dying, and (4) wants to kill him/herself now. In addition to active suicide attempts, indirect self-destructive behavior can be manifested as food refusal, noncompliance with medical care, or carelessness (Beck et al., 1988). Questions from Beck’s scale for suicidal ideation address indirect self-destructive behavior by querying whether the patient deliberately ignores taking care of his/her health, feels like trying to die or by eating too little, or by not taking medication, or by leaving life to chance by carelessly crossing a busy street or driving recklessly.
PHARMACOTHERAPY OF DEPRESSION IN OLDER ADULTS: BENEFITS AND HAZARDS Major depression in later life can be effectively treated with antidepressant pharmacotherapy, particularly if a systematic approach is used and if the clinician, patient, and family care givers persist (Mulsant et al., 2014). The primary goals of treatment encompass both remission and recovery, to lessen caregiver burden, and to facilitate appropriate use of medical and social casework services. To achieve and sustain recovery, it is necessary to prevent relapse and recurrence of major depressive episodes. Maintenance treatment has been shown to modify risk for recurrence and may delay, attenuate, or prevent downstream consequences of depression in older adults, which include dementia and death (from suicide and due to medical causes) (Reynolds et al., 2006). Evidencebased treatment of major depression in older primary care adults has been shown to extend lifespan as well as health span (Gallo et al., 2013), with a 24% reduction in mortality risk over 8–9 years of follow-up, secondary to deaths attributed to cancer. As yet there is no direct experimental evidence that treating depression modifies the risk for dementia, although population-based data show that the longer a person is treated with an antidepressant, the closer his or her risk of dementia comes to the risk of those who have never been depressed. Remission is the first goal of MDD therapy, because response without remission is associated with disabling symptoms, higher risk for relapse and recurrence, impaired psychosocial functioning, and higher levels
ASSESSMENT AND TREATMENT OF MAJOR DEPRESSION IN OLDER ADULTS of healthcare use. There are no known differences in short-term efficacy across different classes of medication. A meta-analysis of response/remission rates to antidepressant drug vs placebo, involving 10 trials and 4165 patients, showed an overall response/remission rate of 44% to drug vs 34% to placebo (OR ¼ 1.40, P < 0.001), with a number needed to treat (NNT) of 13 (Nelson et al., 2008). A recent systematic review indicated that older adults with depression derived significantly greater benefit from combined therapy [cognitive behavioral therapy (CBT) plus pharmacotherapy] compared to pharmacotherapy or psychotherapy alone (Cuijpers et al., 2012). Evidenced-based psychosocial treatments for late-life depression include two learningbased approaches (CBT and problem solving therapy; PST), together with interpersonal psychotherapy (IPT). There remains a paucity of controlled evidence for the management of treatment-resistant depression. The largest placebo-controlled study to date demonstrated efficacy for augmenting venlafaxine (doses up to 300 mg daily) with aripiprazole (2–15 mg daily) in older adults who responded only partially to venlafaxine (44% remission in aripiprazole-randomized vs 29% remission in placebo-randomized participants; NNT ¼ 6.6). The same study demonstrated good safety and tolerability for aripiprazole including absent effects on measures of cardiac function, metabolic markers such as glucose and lipids, and adiposity (i.e., fat gain), and only mild neurologic side effects (Lenze et al., 2015). Aripiprazole-randomized
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participants showed mild akathisia (usually transient and responsive to dose lowering) and some had mild signs of Parkinsonism, but no dyskinesia after a total exposure of 24 weeks. There was greater and faster reduction of suicidal ideation among aripiprazole- than placeboaugmented participants. While aripiprazole augmentation is the only pharmacotherapy option that has been rigorously tested for treatment-resistant depression in older adults, many antidepressant augmentation and switch options exist, based on studies in young adults as well as smaller studies in older adults. In Fig. 23.1, we present a treatment algorithm for antidepressant management in older adults. The algorithm places emphasis on giving adequate trials of medications in dose and duration prior to switching, on personalizing care based on the patient’s prior response and preference, and on safety. The medication strategies in this figure should be integrated with appropriate nonpharmacologic strategies, including recommendations for regular exercise, social support, and psychotherapy and guided self-help (i.e., bibliotherapy) in cognitively intact individuals. In a further analysis of clinical factors that may moderate response to augmentation pharmacotherapy with aripiprazole (Kaneriya Shriya et al., 2016), the authors found that preserved set shifting capacity on the Trails A and B tests (a measure of cognitive flexibility within the spectrum of executive functioning) moderated a higher remission rate with aripiprazole. By contrast, severity of anxiety emerged as a general prognostic factor
Suggested antidepressant algorithm for older adults SSRI/SNRI for first 1–2 trials
Guiding principles: • Personalize treatment based on prior trials: – Don’t retry a drug class (e.g., SSRIs) that already failed an adequate trial. – Don’t retry a specific med if intolerant – DO retry a specific med that worked previously
+ or Δ bupropion (XL), mirtazapine, vilazodone or vortioxetine + second generation antipsychotic (aripiprazole or quetiapine) • + or Δ TCA (nortriptyline), + lithium, esketamine, or T3
•
Neurostimulation: TMS, ECT + = augment for partial responder • Δ = switch for nonresponder TCA, tricyclic antidepressant; T3, liothyronine; TMS, transcranial magnetic stimulation; ECT, electroconvulsive therapy Fig. 23.1. Pharmacotherapy algorithm for treating late life depression.
Avoid drug interactions and known risks – paroxetine + bupropion – Tertiary amine TCAs
Give an adequate trial (4+ weeks at effective dose) and maximize dose as tolerated prior to augmenting or switching. Consider adding psychotherapy if cognitively intact.
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(that is, predictive of poorer remission rates overall with either aripiprazole or with placebo), but not as a specific response modifier. Comorbid medical burden was neither a moderator nor general prognostic factor in this shortterm treatment trial. In our earlier study of 2-year maintenance pharmacotherapy with paroxetine, we observed a moderating role for severity of medical comorbidity, with greater multimorbidity associated with a more brittle long-term response and thus higher rates of depression recurrence (Reynolds et al., 2006). Our observation of a moderating effect of set shifting capacity may converge with the underlying neuropharmacologic mechanisms of action of aripiprazole, involving dopamine receptors in the frontostriatal circuits. Greater integrity of these circuits and of dopamine activity seems critical to both antidepressant efficacy and set shifting. In the context of experimental interventions, we are conducting a randomized, placebo-controlled trial to test the hypothesis that buprenorphine may have antidepressant activity in older adults with treatment-resistant depression. Buprenorphine is a kappa-opiate receptor antagonist and mu-opiate receptor partial agonist. Our recent open-label trial in older adults with partial response to venlafaxine found buprenorphine to be safe and effective (Karp et al., 2014). The hazards of short-term antidepressant pharmacotherapy in older adults include sedative and anticholinergic effects (especially with tricyclic antidepressants or paroxetine), falls, fractures, hyponatremia, and a dosedependent increase in arrhythmia with citalopram (torsade de pointes) (Medwatch, 2010). Drug–drug interactions also should be considered, especially with monoamine oxidase inhibitors, as well as with anticoagulants and antiplatelet agents. Discontinuation due to adverse effects (including fatigue, insomnia, gastrointestinal symptoms, headaches, genitourinary symptoms, and sweating) ranges from 8% to 27% (OR of 1.84 relative to placebo) (Nelson et al., 2008). With respect to continuation and maintenance treatment of depression in the elderly, a systematic review and meta-analysis of double-blind, placebo-controlled randomized trials of antidepressants showed an NNT of 3.4, considerably better for relapse and recurrence prevention than for initial remission (Kok et al., 2011). The authors have shown that both nortriptyline and paroxetine have long-term benefit in recurrence prevention, as compared with pill placebo (Reynolds et al., 1999, 2006). Response tends to be more brittle, with higher rates of recurrence, in those with greater medical comorbidity or comorbid anxiety. The addition of donepezil, a cholinesterase inhibitor (ChEI), to maintenance antidepressant pharmacotherapy improved performance on cognitive tests and cognitive instrumental activities of daily living and reduced the rate of conversion from
MCI to dementia over a 1-year period. However, exposure to the ChEI also increased risk for recurrent depression (possibility related to cholinergic supersensitivity in depression) (Reynolds et al., 2011). We therefore recommend avoiding ChEI in older adults with major depression in most cases. Adverse effects of long-term antidepressant pharmacotherapy may include osteoporosis, orthostatic hypotension, cardiac arrhythmias (especially with tricyclic antidepressants and venlafaxine), anticholinergic effects with worsening of cognitive performance, and falls. On the whole, however, the benefits clearly outweigh the risks in those with a major depression. More specifically, if an antidepressant is effective in bringing about remission from depression in an older adult, their long-term health risks are probably much greater from stopping the medication (and likely precipitating relapse of depression) than maintaining the medication for the long term. Supporting this assertion, the follow-up study by Gallo et al. (2013) of the Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) study (Bruce et al., 2004) showed that a depression care manager working with primary care physicians to provide evidence-based, step-wise algorithmic care for depression reduces mortality risk at 8-year follow-up by 24%, secondary to reduced deaths from cancer. To place this finding in further context: while prospective studies had consistently shown a relationship between depression and mortality in older adults, no randomized trials prior to the 2013 Gallo et al. follow-up had reported that treatment actually prolongs life. In conclusion, major depression in older adults is treatable not only acutely (to bring about remission), but also on a continuing and maintenance basis (to prevent relapse and recurrence and to sustain recovery). While pharmacotherapy tends to be the mainstay of such treatment, combination treatment also utilizing depressionspecific psychotherapies (such as CBT, IPT, or PST) is probably optimal for acute treatment and may also prevent recurrence in “younger old” patients. All patients are appropriate candidates for 6–12 months of continuation of treatment following their initial remission (using the same dose of medication as during acute phase pharmacotherapy). Most patients, including those with single depressive episodes, may also benefit from longer-term maintenance (2+ years) to prevent recurrence and to attenuate downstream consequences of recurrent depression. Evidence-based treatment of depression in old age reduces risk of suicide and may reduce long-term mortality from cancer. Two major unanswered questions are whether treatment of depression reduces the risk of dementia and whether depression treatment slows cellular aging, such as telomere attrition. While it seems likely that depression is a
ASSESSMENT AND TREATMENT OF MAJOR DEPRESSION IN OLDER ADULTS modifiable risk factor for dementia, it has not yet been demonstrated experimentally that evidence-based treatment actually delays, attenuates, or prevents dementia. Pending the availability of such evidence, it seems clinically and ethically appropriate to offer patients maintenance treatment to prolong health span and to maximize cognitive fitness for as long as possible. This should be a matter of shared decision-making, involving both patients and family care givers in a conversation about the short- and long-term goals of care.
ACKNOWLEDGMENTS This study is supported in part by grant P30 MH090333 and the UPMC Endowment in Geriatric Psychiatry.
REFERENCES Agudelo C, Aizenstein HJ, Karp JF et al. (2015). Applications of magnetic resonance imaging for treatment-resistant latelife depression. Dialogues Clin Neurosci 17: 151–169. Beck AT, Steer RA, Ranieri WF (1988). Scale for suicide ideation: psychometric properties of a self-report version. J Clin Psychol 44: 499–505. Bruce ML, Ten Have TR, Reynolds 3rd CF et al. (2004). Reducing suicidal ideation and depressive symptoms in depressed older primary care patients: a randomized controlled trial. JAMA 291: 1081–1091. Butters MA, Whyte EM, Nebes RD et al. (2004). The nature and determinants of neuropsychological functioning in late-life depression. Arch Gen Psychiatry 61: 587–595. Cuijpers P, Reynolds 3rd CF, Donker T et al. (2012). Personalized treatment of adult depression: medication, psychotherapy, or both? A systematic review. Depress Anxiety 29: 855–864. Diniz BS, Butters MA, Albert SM et al. (2013). Late-life depression and risk of vascular dementia and Alzheimer’s disease: systematic review and meta-analysis of community-based cohort studies. Br J Psychiatry 202: 329–335. Gallo JJ, Morales KH, Bogner HR et al. (2013). Long term effect of depression care management on mortality in older adults: follow-up of cluster randomized clinical trial in primary care. BMJ 346: f2570. Harman JS, Schulberg HC, Mulsant BH et al. (2001). The effect of patient and visit characteristics on diagnosis of depression in primary care. J Fam Pract 50: 1068. Kaneriya Shriya H, Robbins-Welty GA, Smagula Stephen F et al. (2016). Predictors and moderators of remission with aripiprazole augmentation in treatment-resistant late-life depression. JAMA Psychiatry 73: 329–336. Karp JF, Butters MA, Begley AE et al. (2014). Safety, tolerability, and clinical effect of low-dose buprenorphine for
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treatment-resistant depression in midlife and older adults. J Clin Psychiatry 75: e785–e793. Kok RM, Heeren TJ, Nolen WA (2011). Continuing treatment of depression in the elderly: a systematic review and meta-analysis of double-blinded randomized controlled trials with antidepressants. Am J Geriatr Psychiatry 19: 249–255. Lenze EJ, Mulsant BH, Blumberger DM et al. (2015). Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial. Lancet 386: 2404–2412. Medwatch (2010). Celexa (citalopram hydrobromide): drug safety communication—abnormal heart rhythms associated with high doses, [Online], U.S. Food and Drug Administration, Washington DC. Available, http://www. fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlerts forHumanMedicalProducts/ucm269481.htmAccessed 02/22/2016 2016. Mulsant BH, Ganguli M (1999). Epidemiology and diagnosis of depression in late life. J Clin Psychiatry 60: 9–15. Mulsant BH, Blumberger DM, Zahinoor I, Rabheru K, Rapoport MJ (2014). A Systematic Approach to Pharmacotherapy for Geriatric Major Depression. Clinics in Geriatric Medicine 30 (3): 517–534. https://doi.org/ 10.1016/j.cger.2014.05.002. Nelson JC, Delucchi K, Schneider LS (2008). Efficacy of second generation antidepressants in late-life depression: a meta-analysis of the evidence. Am J Geriatr Psychiatry 16: 558–567. Reynolds 3rd CF, Dew MA, Pollock BG et al. (2006). Maintenance treatment of major depression in old age. N Engl J Med 354: 1130–1138. Reynolds 3rd CF, Butters MA, Lopez O et al. (2011). Maintenance treatment of depression in old age: a randomized, double-blind, placebo-controlled evaluation of the efficacy and safety of donepezil combined with antidepressant pharmacotherapy. Arch Gen Psychiatry 68: 51–60. Reynolds CF, Frank E, Perel JM et al. (1999). Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression—a randomized controlled trial in patients older than 59 years. JAMA 281: 39–45. Shear MK (2015). Clinical practice. Complicated grief. N Engl J Med 372: 153–160. Spitzer RL, Kroenke K, Williams JB (1999). Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary care evaluation of mental disorders. Patient health questionnaire. JAMA 282: 1737–1744. Szanto K, Gildengers A, Mulsant BH et al. (2002). Identification of suicidal ideation and prevention of suicidal behaviour in the elderly. Drugs Aging 19: 11–24.
Chapter 23
Assessment and treatment of major depression in older adults CHARLES F. REYNOLDS III1*, ERIC LENZE2, AND BENOIT H. MULSANT3 1 University of Pittsburgh School of Medicine, Pittsburgh, PA, United States 2 3
Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
Department of Psychiatry, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
Abstract Late life depression is a significant public health problem as well as a burden on patients, their families, and caregivers. There are significant associations of late life depression with medical disorders and cognitive impairment, the latter due to effects of the depression itself or association with dementia. Diagnostic criteria and screening tests have continued to evolve and provide structure and guidelines for assessment. Accurate diagnosis and treatment are of utmost importance to improve quality of life, alleviate suffering, and prevent suicide. A number of effective antidepressant medications are available; combination therapy with these medications and cognitive behavioral therapy appear most efficacious, and maintenance therapy can decrease the chances of remission. A sequence for treatment of late life depression is provided, with strategies for treatment-resistant depression. The relationship of dementia to depression and the interaction of depression with mechanisms of aging are major foci of research.
This chapter begins with a review of the public health of and clinical significance of depression in older adults. Depression is a risk factor for both Alzheimer’s disease (AD) and vascular dementia. It imposes multiple burdens upon its victims and their family care givers, amplifying the disabilities of medical comorbidities and neurologic illness. The clinical signature of depression in later life is its coexistence with medical illness, resulting in an amplification of disability and suffering, foreshortening of life expectancy, and worsening of caregiver burden. Cognitive impairments are also a core feature of clinical depression in older adults, reflecting the toxic effects of depression on brain health. Here we consider the differential diagnosis of depression in later life, including a variety of approaches that are in use in general medical and neurologic practice. The major risk is underdiagnosis and attendant failure to provide adequate treatment. We also review evidence-based approaches to treatment, together with the limitations of the evidence, and we underscore the importance of taking a long-term view of treatment. Getting well is important but not enough; it is staying well that counts because depression in older adults is often a chronic, relapsing illness.
CLINICAL AND PUBLIC HEALTH PERSPECTIVE ON MAJOR DEPRESSION IN LATER LIFE The public health burden of depression in older adults is reflected in suffering and disability (particularly depression’s amplification of disability associated with concurrent medical and neurologic disorders), increased caregiving burden for family members, greater utilization of healthcare resources (as a result of depression not being recognized or adequately treated), increased risk of all-cause mortality and of suicide, and increased risk of AD and vascular dementia. At the same time, advances in intervention science have demonstrated that major depression in older adults can be treated to remission and that remission can be sustained with appropriate maintenance treatment. The latter point deserves emphasis because depression in older adults often follows a relapsing, chronic course unless adequately treated acutely and long term. Factors contributing to a chronic relapsing course are, variously, psychosocial in nature (e.g., bereavement, social role changes, social isolation),
*Correspondence to: Charles F. Reynolds III, MD, 758 Bellefield Towers, 3811 O’Hara Street, Pittsburgh, PA, 15213, United States. Tel: +1-412-246-6440, E-mail: [email protected]
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sleep- and pain-related, secondary to cerebrovascular disease and neurodegenerative disorders, reflective of limited access to adequate treatment, increasing functional disability, and finally, possibly a manifestation, or cause, of accelerated cognitive aging as well as cellular and molecular aging (e.g., accelerated telomere attrition).
CLINICAL PRESENTATION AND DIAGNOSIS The differential diagnosis of depression in older adults (aged 60 and older) encompasses major depressive disorder (MDD), bipolar disorder, minor depression, bereavement (including prolonged or complicated grief ), adjustment disorder, mood disorders related to a general medical condition, substance-induced mood disorder, and dementia with depressed mood. This differential diagnosis highlights the signatures of major depression in older adults, namely, its concurrence with medical comorbidity and cognitive impairment. Major depression in older adults usually does not present “in pure culture,” but rather with concurrent medical, neurologic, and psychosocial issues. The core features of a major depressive episode in DSM-5 (Diagnostic and Statistical Manual, Fifth edition, of the American Psychiatric Association) include depressed mood or loss of pleasure (anhedonia), together with at least four other symptoms: loss (or increase) of appetite or weight; insomnia or hypersomnia; psychomotor agitation or retardation (observable by others); fatigue or loss of energy; worthlessness or guilt; diminished ability to think, concentrate, or make decisions; and recurrent thoughts of death, passive or active suicidal ideation. Depressed mood and anhedonia are the two core symptoms, and when both are absent, a definitive diagnosis cannot be made. Symptoms must be present for 2 weeks or longer, nearly every day, and most of the day, and they must be of such severity as to be distressing or to interfere with functioning. Two screening questions for depression are based on the Patient Health Questionnaire-2 (PHQ-2): how often has the patient been bothered over the past 2 weeks by either (1) little interest or pleasure in doing things; or (2) feeling down, depressed, or hopeless (Spitzer et al., 1999). When a patient presents with depressive symptoms or a clinical meaningful depression is suspected, Step 1 of a diagnostic algorithm is to assess whether the patient meets criteria for a major depressive episode. Step 2 encompasses an assessment of medical and psychosocial context: including substance misuse, general medical condition co-occurring with depression, vascular or Alzheimer’s dementia, death of a loved one (or other recent stressors), and past history or recurrent major depressive or bipolar disorder episodes. Step 3, in the absence of a major depressive episode, but with distress or impairment, could assess an adjustment disorder or minor depression. In DSM 5 the bereavement exclusion has
been dropped, suggesting that a major depressive episode can be diagnosed within the first 2 months after bereavement if diagnostic criteria are met. In DSM-IV, a major depressive episode was not diagnosable until 2 months after the loss, in recognition of the overlap between acute grief and depression, in order to avoid pathologizing (medicalizing) normal grief. In DSM 5 depression is diagnosable at any point after the loss if diagnostic criteria are met. In other words, the DSM 5 Task Force concluded that bereavement does not “immunize” against depression. “Persistent complex bereavement disorder” (also known as “complicated grief”) is listed in Section III of DSM 5 as a condition for further study. As of now, there is no consensus about the best diagnostic criteria. [Readers interested in this topic are referred to Katherine Shear’s clinical review in the New England Journal of Medicine (Shear, 2015).] Challenges in interpreting diagnostic features of depression in older adults arise because of overlaps in clinical presentation. For example, loss of pleasure (anhedonia) should be distinguished from the apathy of dementia or other neurologic conditions. Loss of appetite or weight can also be seen in concurrent physical illness or with dementia. Sleep disturbances, such as insomnia, also occur with chronic pain and with many physical illnesses, including breathing-related sleep disorders such as obstructive sleep apnea (which should be considered in the differential diagnosis of depression in older adults with sleep disturbances). Psychomotor retardation can be characteristic of neurologic illnesses, similar to the inability to think, concentrate, or to make decisions. Worthlessness and thoughts of death occur at the end of life, with terminal illness. Depression as a manifestation of physical or neurologic illness is common in such conditions as Parkinson’s disease (PD); in the wake of cerebrovascular disease (e.g., stroke); with metabolic conditions (e.g., vitamin B12 deficiency), endocrine conditions (e.g., thyroid and adrenal diseases), autoimmune conditions (e.g., lupus), in viral and other infections (e.g., hepatitis, HIV), and in certain cancers (e.g., pancreas) or with space-occupying lesions. The complexity of clinical phenotypes has generated several approaches to diagnosing depression in the context of concurrent medical and neurologic disease: (1) the exclusive approach does not consider neurovegetative symptoms in the diagnosis; for instance, in a patient with cancer, changes in sleep, energy, appetite, or weight would not be considered when making a diagnosing depression; (2) the substitutive approach replaces neurovegetative symptoms with other or additional cognitive symptoms; for instance, a neurovegetative symptom like weight loss is not considered when diagnosing a depression, but both feelings of guilt and worthlessness can be counted towards the five symptoms required to diagnose a major depressive episode; (3) the etiologic approach evaluates each symptom separately as to pathogenesis;
ASSESSMENT AND TREATMENT OF MAJOR DEPRESSION IN OLDER ADULTS for instance, in a cancer patient, the clinician makes a clinical judgment on whether a specific neurovegetative symptom (eg., weight loss) is caused by the cancer or whether it should be attributed to a depressive disorder; and finally, (4) the inclusive approach counts all depressive symptoms as present, regardless of their potential (and multiple) causes (Mulsant and Ganguli, 1999). The inclusive approach maximizes sensitivity and may be most useful clinically with respect to recognizing depression and implementing treatment, together with interventions for concurrent medical and neurologic disorders. Our opinion is that concurrent intervention for both depression and concurrent medical disorders puts the odds in the patient's favor toward optimal health related quality of life. Several features help to distinguish depression in older adults. In late life, depression amplifies disability and suffering, exacerbates physical symptoms such as pain, worsens cognitive impairment, drives utilization of healthcare resources, and increases risk for early medical mortality and for suicide. The most specific signatures of depression in older adults include the medical and psychosocial context in which it occurs: cognitive impairment, age of onset, concurrent physical and neurologic illnesses, and psychotic features. Because of the phenotypic complexity, detection of depression in primary care remains a challenge, in part because other medical conditions cloud the diagnosis, and because older people are more likely to present with pain and other somatic symptoms. They are also less likely to use the word “depressed” and instead may complain of poor sleep, worrying, and not enjoying or seeing the point of life. After controlling for presenting symptoms, according to the National Ambulatory Medical Care Survey (NAMCS), depression is 56% less likely to be diagnosed in older patients, 37% less likely to be diagnosed in African-Americans, and 35% less likely in Medicaid patients (Harman et al., 2001). The main reasons that a diagnosis of depression may be missed in an older primary care patient are, first, that the older adult does not report or denies depressed mood, but rather may focus on somatic symptoms. Also, the clinician may choose to focus on seemingly more urgent physical problems that compete for attention. The clinician may discount depressive symptoms because they make sense in the psychosocial context of the patient’s life or because they may seem to be attributable to a somatic illness. S/he may further be concerned about not offending the patient or family by using a stigmatized, and stigmatizing, word (depression). To avoid an “I am not depressed” response and barrier to treatment, it is helpful to use words from the patient’s own speech (“worrying,” “not sleeping,” “stressed,” etc.) and, almost always, to seek the perspectives of family caregivers and gain their assistance with treatment initiation and adherence.
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In this context of strategies to enhance recognition, the clinician may find it useful to detect the following clues in an ambulatory patient: (1) help-seeking, with persistent complaints of pain, fatigue, and insomnia as well as multiple diffuse symptoms; and (2) frequent calls and visits to the physician (high utilization of services). Additional clues in hospitalized patients include a recent history of coronary artery bypass surgery, myocardial infarction, stroke, or hip fracture; delayed recovery, treatment refusal, and discharge refusal. Among nursing home residents, additional clues to depression include apathy, withdrawal and isolation, failure to thrive, agitation, delayed rehabilitation, increasing dependency, and refusal to eat or drink (considered as a form of passive suicidal behavior). Blood tests that can be useful when assessing an older person with a depressive syndrome include the following: (1) TSH (hypothyroidism), (2) B12 and folate levels, (3) complete blood count with differential, (4) sodium (hyponatremia), (5) liver function tests (indirect evidence of alcohol use disorder), (6) fasting blood glucose, (7) serum creatinine, (8) serum albumin (to assess nutritional status), and (9) parathyroid hormone and vitamin D levels.
LINKS BETWEEN DEPRESSION AND DEMENTIA There are several links, or pathways, interconnecting depressive symptoms and dementia. Depression is now recognized as a risk factor for dementia, as well as a prodromal expression of dementia and as a presenting symptom of dementia (Diniz et al., 2013). There is a bidirectional relationship between cognitive impairment and depression in later life, such that depressive symptoms and clinical depression are common in patients with dementia; and, conversely, cognitive impairment and dementia are common in patients with clinical depression. In the older population generally, the crosssectional prevalence of clinical depression is about 4%, but it is substantially higher in persons with neurologic illness, with conservative estimates of 20% in AD and in stroke, 40% in Huntington’s disease, and 50% in PD. Helpful distinguishing features in AD include apathy and agitation, sundowning, weight loss without loss of appetite, a tendency to minimize or deny cognitive impairment despite the presence of impaired memory and executive dysfunction, and aphasia and apraxia. In contrast, the hallmarks of depression in older adults are anhedonia and anxiety, sleep disturbance, appetitive disturbance with weight loss, and subjective complaints of cognitive impairment with frequent “I don’t know” responses, in the presence of intake motor and language skills (Butters et al., 2004). Cognitive impairments in older depressed patients are nonetheless common and
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broad-based, in particular slowing of information processing speed and decrements in visuospatial ability, episodic memory, and executive functioning.
POSSIBLE ETIOLOGIC PATHWAYS LINKING COGNITIVE DISORDERS AND DEPRESSION IN LATER LIFE Depression may be an early psychologic reaction to subclinical cognitive decline, thus representing a grief reaction to the loss of the self. Depression may also cause cognitive impairment and lower the threshold for the diagnosis of dementia. Cerebrovascular pathology may lead to both “vascular depression” (see following text) and to vascular dementia. Loss of noradrenergic neurons due to AD pathology may manifest as prodromal depression at the onset of dementia. Depression appearing for the first time in later life (late-onset) is frequently accompanied by a lower likelihood of a family history and may in fact be a prodromal expression of AD or as a manifestation of cerebrovascular disease (termed “vascular depression”). Late-onset depression also occurs in the context of other medical and psychosocial issues, such as those that accompany the end of life. Pathways to depression may involve disruption of neurotransmitters or of neural circuits (e.g., as in stroke, Parkinson’s, or Alzheimer’s), physiologic stress (e.g., post coronary artery bypass graft (CABG) or post-MI), as a consequence of functional disability (following hip fracture or renal failure), or in the wake of psychosocial stresses (such as attachment bereavement or transitions in major social roles, such as retirement). Depression in older adults is often multifactorial. Possible pathways include monoamine deficiencies, circadian rhythm disruption, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, inflammation (pro-inflammatory cytokines, which stimulate the HPA axis and monoamine activity in the brain), and vascular insufficiency with hypoperfusion. Vascular disease may predispose, precipitate, or perpetuate the symptoms and signs of late-life depression, including cognitive deficits, psychomotor retardation, lack of insight, and disability out of proportion to the severity of the depression. White matter lesions, seen on magnetic resonance imaging as white matter hyperintensities, are characteristic of the construct of “vascular depression” and of its clinical expression as a depression–executive dysfunction syndrome (Agudelo et al., 2015).
SUICIDE IN LATE-LIFE DEPRESSION Suicide in later life is one of depression’s most tragic consequences, not only for the victim, but also for family members and other “informal” care givers. It is a
reminder that depression can be a lethal illness. Suicidal ideation can be active or passive, e.g., refusing treatment. Older adults, especially white males, have some of the highest suicide rates in North America, with higher intent and likelihood of completion by the use of violent methods (e.g., hanging, firearms) being more common than nonviolent methods (Szanto et al., 2002). Four clinically useful screening questions address whether the patient (1) cares if s/he lives or dies, (2) wants to die now, (3) thinks that reasons for staying alive are better than the reasons for dying, and (4) wants to kill him/herself now. In addition to active suicide attempts, indirect self-destructive behavior can be manifested as food refusal, noncompliance with medical care, or carelessness (Beck et al., 1988). Questions from Beck’s scale for suicidal ideation address indirect self-destructive behavior by querying whether the patient deliberately ignores taking care of his/her health, feels like trying to die or by eating too little, or by not taking medication, or by leaving life to chance by carelessly crossing a busy street or driving recklessly.
PHARMACOTHERAPY OF DEPRESSION IN OLDER ADULTS: BENEFITS AND HAZARDS Major depression in later life can be effectively treated with antidepressant pharmacotherapy, particularly if a systematic approach is used and if the clinician, patient, and family care givers persist (Mulsant et al., 2014). The primary goals of treatment encompass both remission and recovery, to lessen caregiver burden, and to facilitate appropriate use of medical and social casework services. To achieve and sustain recovery, it is necessary to prevent relapse and recurrence of major depressive episodes. Maintenance treatment has been shown to modify risk for recurrence and may delay, attenuate, or prevent downstream consequences of depression in older adults, which include dementia and death (from suicide and due to medical causes) (Reynolds et al., 2006). Evidencebased treatment of major depression in older primary care adults has been shown to extend lifespan as well as health span (Gallo et al., 2013), with a 24% reduction in mortality risk over 8–9 years of follow-up, secondary to deaths attributed to cancer. As yet there is no direct experimental evidence that treating depression modifies the risk for dementia, although population-based data show that the longer a person is treated with an antidepressant, the closer his or her risk of dementia comes to the risk of those who have never been depressed. Remission is the first goal of MDD therapy, because response without remission is associated with disabling symptoms, higher risk for relapse and recurrence, impaired psychosocial functioning, and higher levels
ASSESSMENT AND TREATMENT OF MAJOR DEPRESSION IN OLDER ADULTS of healthcare use. There are no known differences in short-term efficacy across different classes of medication. A meta-analysis of response/remission rates to antidepressant drug vs placebo, involving 10 trials and 4165 patients, showed an overall response/remission rate of 44% to drug vs 34% to placebo (OR ¼ 1.40, P < 0.001), with a number needed to treat (NNT) of 13 (Nelson et al., 2008). A recent systematic review indicated that older adults with depression derived significantly greater benefit from combined therapy [cognitive behavioral therapy (CBT) plus pharmacotherapy] compared to pharmacotherapy or psychotherapy alone (Cuijpers et al., 2012). Evidenced-based psychosocial treatments for late-life depression include two learningbased approaches (CBT and problem solving therapy; PST), together with interpersonal psychotherapy (IPT). There remains a paucity of controlled evidence for the management of treatment-resistant depression. The largest placebo-controlled study to date demonstrated efficacy for augmenting venlafaxine (doses up to 300 mg daily) with aripiprazole (2–15 mg daily) in older adults who responded only partially to venlafaxine (44% remission in aripiprazole-randomized vs 29% remission in placebo-randomized participants; NNT ¼ 6.6). The same study demonstrated good safety and tolerability for aripiprazole including absent effects on measures of cardiac function, metabolic markers such as glucose and lipids, and adiposity (i.e., fat gain), and only mild neurologic side effects (Lenze et al., 2015). Aripiprazole-randomized
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participants showed mild akathisia (usually transient and responsive to dose lowering) and some had mild signs of Parkinsonism, but no dyskinesia after a total exposure of 24 weeks. There was greater and faster reduction of suicidal ideation among aripiprazole- than placeboaugmented participants. While aripiprazole augmentation is the only pharmacotherapy option that has been rigorously tested for treatment-resistant depression in older adults, many antidepressant augmentation and switch options exist, based on studies in young adults as well as smaller studies in older adults. In Fig. 23.1, we present a treatment algorithm for antidepressant management in older adults. The algorithm places emphasis on giving adequate trials of medications in dose and duration prior to switching, on personalizing care based on the patient’s prior response and preference, and on safety. The medication strategies in this figure should be integrated with appropriate nonpharmacologic strategies, including recommendations for regular exercise, social support, and psychotherapy and guided self-help (i.e., bibliotherapy) in cognitively intact individuals. In a further analysis of clinical factors that may moderate response to augmentation pharmacotherapy with aripiprazole (Kaneriya Shriya et al., 2016), the authors found that preserved set shifting capacity on the Trails A and B tests (a measure of cognitive flexibility within the spectrum of executive functioning) moderated a higher remission rate with aripiprazole. By contrast, severity of anxiety emerged as a general prognostic factor
Suggested antidepressant algorithm for older adults SSRI/SNRI for first 1–2 trials
Guiding principles: • Personalize treatment based on prior trials: – Don’t retry a drug class (e.g., SSRIs) that already failed an adequate trial. – Don’t retry a specific med if intolerant – DO retry a specific med that worked previously
+ or Δ bupropion (XL), mirtazapine, vilazodone or vortioxetine + second generation antipsychotic (aripiprazole or quetiapine) • + or Δ TCA (nortriptyline), + lithium, esketamine, or T3
•
Neurostimulation: TMS, ECT + = augment for partial responder • Δ = switch for nonresponder TCA, tricyclic antidepressant; T3, liothyronine; TMS, transcranial magnetic stimulation; ECT, electroconvulsive therapy Fig. 23.1. Pharmacotherapy algorithm for treating late life depression.
Avoid drug interactions and known risks – paroxetine + bupropion – Tertiary amine TCAs
Give an adequate trial (4+ weeks at effective dose) and maximize dose as tolerated prior to augmenting or switching. Consider adding psychotherapy if cognitively intact.
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(that is, predictive of poorer remission rates overall with either aripiprazole or with placebo), but not as a specific response modifier. Comorbid medical burden was neither a moderator nor general prognostic factor in this shortterm treatment trial. In our earlier study of 2-year maintenance pharmacotherapy with paroxetine, we observed a moderating role for severity of medical comorbidity, with greater multimorbidity associated with a more brittle long-term response and thus higher rates of depression recurrence (Reynolds et al., 2006). Our observation of a moderating effect of set shifting capacity may converge with the underlying neuropharmacologic mechanisms of action of aripiprazole, involving dopamine receptors in the frontostriatal circuits. Greater integrity of these circuits and of dopamine activity seems critical to both antidepressant efficacy and set shifting. In the context of experimental interventions, we are conducting a randomized, placebo-controlled trial to test the hypothesis that buprenorphine may have antidepressant activity in older adults with treatment-resistant depression. Buprenorphine is a kappa-opiate receptor antagonist and mu-opiate receptor partial agonist. Our recent open-label trial in older adults with partial response to venlafaxine found buprenorphine to be safe and effective (Karp et al., 2014). The hazards of short-term antidepressant pharmacotherapy in older adults include sedative and anticholinergic effects (especially with tricyclic antidepressants or paroxetine), falls, fractures, hyponatremia, and a dosedependent increase in arrhythmia with citalopram (torsade de pointes) (Medwatch, 2010). Drug–drug interactions also should be considered, especially with monoamine oxidase inhibitors, as well as with anticoagulants and antiplatelet agents. Discontinuation due to adverse effects (including fatigue, insomnia, gastrointestinal symptoms, headaches, genitourinary symptoms, and sweating) ranges from 8% to 27% (OR of 1.84 relative to placebo) (Nelson et al., 2008). With respect to continuation and maintenance treatment of depression in the elderly, a systematic review and meta-analysis of double-blind, placebo-controlled randomized trials of antidepressants showed an NNT of 3.4, considerably better for relapse and recurrence prevention than for initial remission (Kok et al., 2011). The authors have shown that both nortriptyline and paroxetine have long-term benefit in recurrence prevention, as compared with pill placebo (Reynolds et al., 1999, 2006). Response tends to be more brittle, with higher rates of recurrence, in those with greater medical comorbidity or comorbid anxiety. The addition of donepezil, a cholinesterase inhibitor (ChEI), to maintenance antidepressant pharmacotherapy improved performance on cognitive tests and cognitive instrumental activities of daily living and reduced the rate of conversion from
MCI to dementia over a 1-year period. However, exposure to the ChEI also increased risk for recurrent depression (possibility related to cholinergic supersensitivity in depression) (Reynolds et al., 2011). We therefore recommend avoiding ChEI in older adults with major depression in most cases. Adverse effects of long-term antidepressant pharmacotherapy may include osteoporosis, orthostatic hypotension, cardiac arrhythmias (especially with tricyclic antidepressants and venlafaxine), anticholinergic effects with worsening of cognitive performance, and falls. On the whole, however, the benefits clearly outweigh the risks in those with a major depression. More specifically, if an antidepressant is effective in bringing about remission from depression in an older adult, their long-term health risks are probably much greater from stopping the medication (and likely precipitating relapse of depression) than maintaining the medication for the long term. Supporting this assertion, the follow-up study by Gallo et al. (2013) of the Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) study (Bruce et al., 2004) showed that a depression care manager working with primary care physicians to provide evidence-based, step-wise algorithmic care for depression reduces mortality risk at 8-year follow-up by 24%, secondary to reduced deaths from cancer. To place this finding in further context: while prospective studies had consistently shown a relationship between depression and mortality in older adults, no randomized trials prior to the 2013 Gallo et al. follow-up had reported that treatment actually prolongs life. In conclusion, major depression in older adults is treatable not only acutely (to bring about remission), but also on a continuing and maintenance basis (to prevent relapse and recurrence and to sustain recovery). While pharmacotherapy tends to be the mainstay of such treatment, combination treatment also utilizing depressionspecific psychotherapies (such as CBT, IPT, or PST) is probably optimal for acute treatment and may also prevent recurrence in “younger old” patients. All patients are appropriate candidates for 6–12 months of continuation of treatment following their initial remission (using the same dose of medication as during acute phase pharmacotherapy). Most patients, including those with single depressive episodes, may also benefit from longer-term maintenance (2+ years) to prevent recurrence and to attenuate downstream consequences of recurrent depression. Evidence-based treatment of depression in old age reduces risk of suicide and may reduce long-term mortality from cancer. Two major unanswered questions are whether treatment of depression reduces the risk of dementia and whether depression treatment slows cellular aging, such as telomere attrition. While it seems likely that depression is a
ASSESSMENT AND TREATMENT OF MAJOR DEPRESSION IN OLDER ADULTS modifiable risk factor for dementia, it has not yet been demonstrated experimentally that evidence-based treatment actually delays, attenuates, or prevents dementia. Pending the availability of such evidence, it seems clinically and ethically appropriate to offer patients maintenance treatment to prolong health span and to maximize cognitive fitness for as long as possible. This should be a matter of shared decision-making, involving both patients and family care givers in a conversation about the short- and long-term goals of care.
ACKNOWLEDGMENTS This study is supported in part by grant P30 MH090333 and the UPMC Endowment in Geriatric Psychiatry.
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