The challenge of restoring functioning in older depressed patients






Cornelius KATONA
MD, FRCPsych
Hon Professor, Division of Psychiatry
University College London
and Medical Director
Helen Bamber Foundation
London, UNITED KINGDOM

The challenge of restoring functioning in older depressed patients


by C. Katona, United Kingdom



Depression is associated with disability, increased mortality—including (but not mainly) from suicide—poorer outcomes from physical illness, and greater use of primary and secondary and social care resources. Despite this, most controlled evaluations of antidepressants and other treatment interventions focus on change in depressive symptoms. It has been suggested that the benefits of antidepressants decrease with age and are no longer clinically significant in the population aged over 65. This paper argues that it would be more appropriate to design clinical trials to focus on change in function rather than on change in depressive symptoms. Parameters relevant to function are identified. These include the tolerability of the treatment, its impact on quality of life (both overall and disease-related), its effects on cognitive functioning, whether it reduces health care costs, whether it prevents relapse and recurrence, and whether it can prevent full-blown depression if given to older people at high risk. The evidence regarding each of these parameters is briefly reviewed. Antidepressants do appear to be quite well tolerated by older people. They are also effective in preventing relapse and recurrence. There is little information on the impact of antidepressant treatment on health care costs, though more complex treatment packages do appear to be cost effective. Preventative approaches show promise in terms of both effectiveness and cost-effectiveness. There is a dearth of evidence regarding measures designed specifically to measure functional response in older depressed patients.

Medicographia. 2014;36:458-463 (see French abstract on page 463)



Depression is associated with disability, increased mortality—including (but not mainly) from suicide—poorer outcomes from physical illness, and greater use of primary and secondary and social care resources. Major depression is a recurring disorder and older people are more at risk of recurrence than the younger population. The likelihood of chronicity or a persistently fluctuating course is worse the more severe the depression.1 The traditional approach to evaluating whether treatments (particularly antidepressants) are efficacious concentrates on measuring change in depressive symptoms. The slightly broader concept of effectiveness usually relies on the same specific outcome measures but relates to how well a treatment works in real clinical practice as opposed to the narrower clinical trial context. In recent years, the gap between effectiveness and efficacy in the context of treatments for depression has narrowed somewhat as trial design has become more “pragmatic” (ie, more like real life practice). This is particularly important for trials in older people since most early antidepressant trials in old age excluded most of the people presenting for treatment because of the near ubiquity—particularly in the “older-old”—of physical comorbidity.

However, despite clinical trials in older people having become more pragmatic, most still adopt symptom relief as the primary outcome measure. Although the two most recently published clinical trials have been positive,2,3 and the largest and most recent meta-analysis to date4 has also shown overall benefits for antidepressants in older people, the effect sizes are often small. One recent meta-analysis5 has suggested that the benefits of antidepressants decrease with age and are no longer clinically significant in the population aged over 65. The authors emphasized that there were relatively few studies in the over 65 population, that the studies they did include were quite heterogeneous, and that functional aspects such asphysical comorbidity and executive dysfunction might have had a particularly adverse effect on outcomes in the 65+ studies.

In view of the apparently modest clinical effects as conventionally measured and the profound effects of depression in old age on day-to-day functioning, it would surely be more appropriate to design clinical trials to focus on change in function rather than on change in depressive symptoms. What components of “function” might be relevant if such an approach were adopted? I would argue that these should include the tolerability of the treatment (in terms of side effect and withdrawal rates), its impact on quality of life (both overall and disease-related), its effects on cognitive functioning (which might be beneficial or adverse), whether it reduces health care costs, whether it prevents relapse and recurrence, and whether it can prevent full-blown depression if given to older people at high risk. Though the evidence base examining effects on these broader parameters remains limited, many of the more recent clinical trials have provided evidence related to functional efficacy and effectiveness. In this paper I will attempt to give a brief overview of that evidence, and thereby highlight the need for further research on the extent to which treating depression in old age can ameliorate clinical functioning. This review focuses particularly on trials of antidepressants (Table I, page 460), though some relevant studies involve psychological treatments and/or examine care packages rather than focusing exclusively on antidepressant treatments alone.




Tolerability

Older depressed people almost invariably have one or more physical illnesses. Many are also taking prescribed (or over the- counter) medications for these illnesses, which may cause adverse interactions when antidepressants are coprescribed. More fundamentally, the pharmacokinetic and pharmacodynamic changes associated with ageing can significantly alter the propensity of antidepressant medication to cause clinically significant side effects. These changes include decreases in lean muscle mass and in passive drug absorption, increases in body fat, and thereby in the elimination half-life of (fat soluble) antidepressants.10 Changes in binding proteins mean that free circulating levels of selective serotonin reuptake inhibitors (SSRIs) are increased but those of tricyclics are lowered. There are also age-related decreases in drug metabolism and excretion. What is less clear is the extent to which these potential problems are clinically significant.

In clinical practice, SSRIs are in fact generally well tolerated by older people, though gastrointestinal (GI) problems such as nausea are common.11 It is not clear, however, whether nausea is more common in older than in younger patients. SSRI related GI bleeding is potentially important in older people since they are in any case at greater risk of such bleeding and are very often coprescribed anti-inflammatory drugs, which carry a high risk of GI bleeding. Other SSRI-related side effects, which may be clinically more relevant in old age, include restlessness, sedation, extrapyramidal movement disorders, and hyponatremia, though the latter is usually mild. Drug interactions involving the cytochrome P450 enzyme system may be clinically relevant in older people; citalopram, escitalopram, and sertraline may carry a relatively low risk in this regard. In the context of clinical trials, adverse event–related withdrawal (AERW) rates may provide the best overall measure of real-life tolerability. Such AERW rates are generally low, though venlafaxine has been found to have a relatively high rate12 (27%, compared with 19% for fluoxetine and 9% for placebo in a three-arm study). Agomelatine, vortioxetine, and duloxetine have all recently been reported as carrying similar risks of AERW to placebo, though in the three-way comparison between vortioxetine, duloxetine, and placebo,3 duloxetine had a slightly higher AERW rate (10% vs 6% on vortioxetine and 3% on placebo).

Cognition

Cognitive dysfunction is an important component of depression in older people that may significantly contribute to functional disability. Cognitive deficits may precede the onset of the depression. Though some degree of cognitive improvement usually accompanies recovery from a depressive episode, the cognitive deficits do not always reverse completely. Persisting cognitive dysfunction may be a prodromal indicator of future dementia. Antidepressant medication may have adverse effects on cognitive function—as was particularly evident in the case of tricyclic antidepressants because of their high anticholinergic potency and the relative lack of cholinergic reserve in the ageing brain.


Table I
Table I. Main findings of recent efficacy trials.

Abbreviations: AD, antidepressant; DUL, duloxetine; HAM-D, Hamilton Depression Scale; MDD, major depressive disorder; n/a, not applicable; PLA, placebo; RCT, randomized controlled trial; VOR, vortioxetine.
After reference 9: Katona et al. Maturitas. 2014; In Press. http://dx.doi.org/10.1016/j.maturitas.2014.05.016. ©2014 Elsevier Inc.



The notion that newer antidepressants might actually enhance cognition independently of their antidepressant effects is a potentially exciting one. Raskin et al13 hypothesized that the serotonin–norepinephrine reuptake inhibitor duloxetine might enhance cognition because of its dual action (blocking reuptake of noradrenaline as well as serotonin). Unusually, their trial was designed with the primary aim of testing this hypothesis and included subjects with mild dementia. The authors developed a trial-specific composite cognitive score using tests previously shown to be most impaired in depression. Their results confirmed that duloxetine improved cognitive function compared with placebo and—more importantly—that the effects of depression were largely (more than 90%) independent of the antidepressant effects that were also evident. More recently these findings were replicated in a three-way comparison between duloxetine, vortioxetine (which has multiple serotonin-enhancing effects), and placebo.3 Both duloxetine and vortioxetine had beneficial (and largely direct) effects on acquisition and delayed recall. Vortioxetine also enhanced speed of processing. Neither study examined whether the effects they identified were clinically significant. Cognitive function has also been examined in a recent trial (Health Technology Assessment Study of the use of Antidepressants for Depression in Dementia [HTA-SADD]) of sertraline and mirtazapine against placebo for depression in Alzheimer’s disease.14 Neither active antidepressant had significant effects on cognition as measured by the Mini Mental State Examination (MMSE) score.

Impact on quality of life

Raskin et al13 examined the effect of duloxetine on a specific aspect of quality of life: pain. They found duloxetine superior to placebo in relieving back pain and total time spent in pain. Similar trends were found for other pain modalities that did not reach statistical significance. This study did not use an overall quality of life measure. The HTA-SADD trial14 examined both generic and dementia-related quality of life in patients with the depression of Alzheimer’s disease and found that neither active drug had significant effects on quality of life. In the IMPACT study (Improving Mood-Promoting Access to Collaborative Treatment),15 which evaluated stepped collaborative care delivered by a care coordinator based in primary care and supporting the patient’s regular primary care clinician, the active intervention showed benefits both in terms of a global measure of quality of life and in terms of function as measured with the Sheehan Disability Scale (SDS). Though this scale has work, social life, and family life subscales, only total scores were reported.

To the best of my knowledge, the only recent trial that has used a function-focused measure of quality of life in evaluating a novel antidepressant on older people is the agomelatine/ placebo study by Heun et al.2 Like the IMPACT study, this study incorporated the SDS scale.16 Agomelatine was associated with improvement in all three (work, social life, and family life) subscales. The authors did not comment on the extent to which these effects were independent of agomelatine’s antidepressant effects.

Effect on health care costs

Katon et al17 found that total outpatient and inpatient costs were about 50% greater for depressed than for nondepressed older patients after allowing for comorbid chronic medical conditions. Most of the costs related to physical rather than mental health care. In the light of this, it is surprising that most recent antidepressant treatment trials in older people do not report on associated health care costs. One exception is the HTA-SADD study of mirtazapine and sertraline in the depression of Alzheimer’s disease, which found that although neither antidepressant was effective, mirtazapine was nonetheless cost effective in terms of reducing informal carer costs.18 This probably reflected its sedative effect.

More complex treatment packages for elderly depressed patients have, however, been subjected to detailed cost analysis, particularly in the United States. Integrated care (ie, care provided in the primary care setting by a behavioral health professional co-located in that setting) was compared with enhanced specialist referral. The integrated care model was found to be cost effective (in terms of number of “depression free days”) in the Veterans Affairs setting but not in other settings.19 In keeping with this, a follow-up of the IMPACT study20 concluded that the intervention evaluated (a stepped collaborative care program based in primary care and supporting the patient’s regular primary care clinician) was associated with sustained costs as well as clinical benefits over a 4-year follow- up.

A stepped care approach to preventing depression in the primary care setting in Holland (discussed in the section on prevention below) has also been shown to be cost effective, based on willingness to pay €5000 for an extra depression or anxiety-free year.21 The cost effectiveness (like clinical effectiveness) of such an approach was not, however, demonstrated in an attempted replication in the nursing-home context.22

Prevention of relapse and recurrence

Most short- and longer-term studies indicate that antidepressants reduce relapse and recurrence rates in patients who have achieved remission on the antidepressant in question. This was clearly demonstrated in high-risk patients (ie, those with several previous episodes) for the tricyclic antidepressant nortriptyline (with or without adjunctive interpersonal psychotherapy [IPT]).23 These findings were replicated for the SSRI paroxetine (again with and without IPT),24 though the latter study included patients who were not at particularly high risk of relapse.

Kok et al25 carried out a systematic review that aimed to include all double-blinded placebo-controlled randomized controlled trials with antidepressant continuation or maintenance treatment of unipolar depression in patients age dover 55years. They excluded studies restricted to patients with bipolar depression, psychotic depression, or depression in the context of specific medical disorders. They also examined tolerability in terns of AERW rates. The authors identified 11 published trials that met their entry criteria. The effect of drug treatment was consistent across the studies. The absolute risk of suffering a relapse or recurrence using antidepressants compared with placebo was reduced by 28%, and the number needed to treat (NNT) to prevent one relapse was 3.6 (2.9 for tricyclics and 4.2 for SSRIs). In the 5 studies in which such data was presented, the AERW rate was 4.2% for antidepressants and 5.1% for placebo.

Prevention in patients at high risk

There has been considerable interest in the potential benefits of identifying people at high risk of, or presenting with, subsyndromal clinical features of depression and intervening to prevent full-blown depression with its associated loss of functional ability, from developing. Such an approach carries par ticular promise in older people because of the high prevalence of subsyndromal depression in this population and the particularly strong association between old age depression and excess mortality from stroke, myocardial infarction, and cancer.

Schoevers et al26 identified the following older people as being at greatest risk of depression and therefore at greatest risk of benefiting from preventative interventions: those with functional limitation as a result of disability such as stroke or macular degeneration, those with limited social networks, and those with subsyndromal depressive symptoms. They concluded that the group in whom prevention might be achieved most efficiently would be those with subsyndromal depressive symptoms.

The evidence to date supports these conclusions. A metaanalysis (not restricted to older people) found that overall, preventative interventions reduced the new incidence of major depression by about 20%.27 A more recent review focusing on preventative trials in older people found that several interventions showed promise.28 These included:
♦ Social support for people who have been spousally bereaved
♦ Multicomponent interventions for dementia caregivers
♦ Problem-solving therapy in people with medical illnesses
♦ Antidepressants following stroke
♦ Stepped-care prevention in primary care

Evidence published since that review has provided further support for the use of some of these interventions. The incidence of depression following stroke was effectively prevented both by low-dose escitalopram and by problem-solving therapy (PST) with an NNT of about 8 for both interventions.29 In primary care patients with subsyndromal anxiety or depression symptoms aged 75 or over, a stepped-care approach was associated with caseness-level incident depression or anxiety in only 11% at 1 year, compared with an incidence of 24% in controls treated as usual. A more recent set of studies has, however, failed to confirm either the clinical benefits or the cost effectiveness of the stepped-care approach in the care-home (as opposed to the community) setting.22

Reynolds et al30 have carried out a detailed conceptual review of the potential benefits of early intervention focusing on whether such benefits might be evident in low- and middle income as well as in high-income countries. They concluded that relatively simple learning-based psychological approaches such as problem-solving therapy may be a particularly attractive option in low- and middle-income countries. The authors expressed misgivings about the preventative use of antidepressants (in contexts other than relapse and recurrence prevention), given the limited evidence for their efficacy in mild depression and the increased vulnerability to antidepressant- related adverse effects (such as falls and hyponatremia) associated with the ageing process. They also highlighted the promise of biomarkers (such as proinflammatory cytokines) in identifying those at highest risk, and of the potential benefits of systematic collection of data on clinical risk markers such as insomnia, social isolation, and physical disability.

Conclusions

Some of the more recent clinical trials of antidepressants and of other interventions have evaluated outcome measures that are more relevant to clinical functioning than changes in depressive symptoms. However, the evidence base for most of these measures is limited. Antidepressants do appear to be quite well tolerated by older people—with some antidepressants showing AERW rates similar to those of placebo. The evidence indicating that antidepressants are effective in preventing relapse and recurrence in patients who remit following initial treatment is also robust.

In contrast, there is little information on the impact of antidepressant treatment on health care costs, though more complex treatment packages do appear to be cost effective. Preventative approaches show promise in terms of both effectiveness and cost effectiveness, but more research is needed. There is a dearth of evidence regarding measures designed specifically to measure functional response in older depressed patients. In this regard, the recent evaluation of agomelatine against placebo by Heun et al2 provides a good precedent for future studies.


References
1. Beekman ATF, Geerlings SW, Deeg DJH, et al. The natural history of late-life depression: a 6-year prospective study in the community. Arch Gen Psychiatry. 2002:59;605-611.
2. Heun R, Ahokas A, Boyer P, et al. The efficacy of agomelatine in elderly patients with recurrent major depressive disorder: a placebo-controlled study. J Clin Psychiatry. 2013:74(6):587-594.
3. Katona C, Hansen T, Olsen CK. A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol. 2012;27(4):215-223.
4. Kok RM, Nolen WA, Heeren TJ. Efficacy of treatment in older depressed patients: a systematic review and meta-analysis of double-blind randomized controlled trials with antidepressants. J Affect Disord. 2012;141(2-3):103-115.
5. Tedeschini E, Levkovitz Y, Iovieno N, et al. Efficacy of antidepressants for latelife depression: a meta-analysis and meta-regression of placebo-controlled randomized trials. J Clin Psychiatry. 2011;72(12):1660-1668.
6. Nelson JC, Delucchi K, Schneider LS. Anxiety does not predict response to antidepressant treatment in late life depression: results of a meta-analysis. Int J Geriatr Psychiatry. 2008;24:539-544.
7. Mukai Y, Tampi RR. Treatment of depression in the elderly: a review of the recent literature on the efficacy of single- versus dual-action antidepressants. Clin Ther. 2009;31(5):945-961.
8. Sneed JR, Rutherford BR, Rindskopf D, Lane DT, Sackeim HA, Roose SP. Design makes a difference: a meta-analysis of antidepressant response rates in placebo-controlled versus comparator trials in late-life depression. Am J Geriatr Psychiatry. 2008;16:65-73.
9. Katona C, Bindman DC, Katona CP. Antidepressants for older people: what can we learn from the current evidence base? Maturitas. 2014; In Press. http://dx. doi.org/10.1016/j. maturitas. 2014.05.016.
10. Rajji TK, Mulsant BH, Lotrich FE, Lokker C, Reynolds. CF Use of antidepres sants in late-life depression. Drugs Aging. 2008;25(10):841-853.
11. Chemali Z, Chahine LM, Fricchione G. The use of selective serotonin reuptake inhibitors in elderly patients. Harv Rev Psychiatry. 2009;17(4):242-253.
12. Schatzberg A, Roose S. A double-blind, placebo-controlled study of venlafaxine and fluoxetine in geriatric outpatients with major depression. Am J Geriatr Psychiatry. 2006;14(4):361-370.
13. Raskin J, Wiltse CG, Siegal A, et al. Efficacy of duloxetine on cognition, depression and pain in elderly patients with major depressive disorder: an 8-week, double- blind, placebo-controlled trial. Am J Psychiatry. 2007;164:900-909.
14. Banerjee S, Hellier J, Dewey M, et al. Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. Lancet. 2011;378:403-411.
15. Unützer J, Katon W, Callahan CM, et al. Improving Mood-Promoting Access to Collaborative Treatment. Collaborative care management of late-life depression in the primary care setting: a randomized controlled trial. JAMA. 2002; 288(22):2836-2845.
16. Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int J Clin Psychopharmacol. 1996;11(suppl 3):89-95.
17. Katon WJ, Lin E, Russo J, Unutzer J. Increased medical costs of a population- based sample of depressed elderly patients. Arch Gen Psychiatry. 2002; 60:897-903.
18. Romeo R, Knapp M, Hellier J, et al. Cost-effectiveness analyses for mirtazapine and sertraline in dementia: randomised controlled trial. Br J Psychiatry. 2013;202:121-128.
19. Wiley-Exley E, Domino ME, Maxwell J, Levkoff SE. Cost-effectiveness of integrated care for elderly depressed patients in the PRISM-E study. J Ment Helath Policy Econ. 2009;12(4):205-213.
20. Unutzer J, Katon WJ, Fan MY, et al. Long-term Cost Effects of Collaborative Care for Late-life. Am J Manag Care. 2008;14:95-100.
21. van’t Veer-Tazelaar P, Smit F, van Hout H, et al Cost-effectiveness of a stepped care intervention to prevent depression and anxiety in late life: randomised trial. Br J Psychiatry. 2010;196:319-325.
22. Bosmans JE, Dozeman E, van Marwijk HW, et al. Cost-effectiveness of a stepped care programme to prevent depression and anxiety in residents in homes for older people: a randomised controlled trial. Int J Geriat Psychiatry. 2014;29(2):182-190.
23. Reynolds CF III, Frank E, Perel JM, et al. Nortriptyline and interpersonal psychotherapy as maintenance therapies for recurrent major depression: a randomized controlled trial in patients older than 59 years. JAMA. 1999;281(1):39-45.
24. Reynolds CF III, Dew MA, Pollock BG, et al. Maintenance treatment of major depression in old age. NEJM. 2006;354:1130-1138.
25. Kok RM, Heeren TJ, Nolen WA. 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. 2011;19(3):249-255.
26. Schoevers RA, Smit F, Deeg DJH, et al. Prevention of late-life depression in primary care: do we know where to begin? Am J Psychiatry. 2006;163:1611-1621.
27. Cuijpers P, van Straten A, Smit F, Mihalopoulos C, Beekman A. Preventing the onset of depressive disorders: a meta-analytic review of psychological interventions. Am J Psychiatry. 2008;165:1272-1280.
28. Cuijpers P, Smit F, Lebowitz DD, Beekman AT. Prevention of Mental Disorders in late life. In: Abou-Saleh MT, Katona C, Kumar A (eds). Principles and Practice of Geriatric Psychiatry. Chichester, UK: Wiley; 2011: 844-849.
29. Robinson RG, Jorge RE, Moser DR, et al. Escitalopram and problem-solving therapy for prevention of poststroke depression: randomised controlled trial. JAMA. 2008;299:2931-2400.
30. Reynolds CF III, Cuijpers P, Patel V, et al. Early intervention to reduce the global health and economic burden of major depression in older adults. Annu Rev Public Health. 2012;33:129-135.


Keywords: antidepressant; depression; function; old age