10 ECT Depresi Resisten.PDF

Drugs Aging 2007; 24 (10): 801-814THERAPY IN PRACTICE 1170-229X/07/0010-0801/$44.95/0

© 2007 Adis Data Information BV. All rights reserved.

Getting Better, Getting WellUnderstanding and Managing Partial and Non-Response toPharmacological Treatment of Non-Psychotic MajorDepression in Old Age

Henry C. Driscoll, Jordan F. Karp, Mary Amanda Dew and Charles F. Reynolds III

Advanced Center for Interventions and Services Research for Late-Life Mood Disorders, and theJohn A. Hartford Center for Excellence in Geriatric Psychiatry, University of Pittsburgh School ofMedicine, Pittsburgh, Pennsylvania, USA

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8011. Challenges of Partial and Non-Response in Late-Life Non-Psychotic Depression . . . . . . . . . . . . . . . . 8022. Selection of Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8033. Short-Term Treatment: Achieving Response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8034. Maintenance and Continuation Treatment: The Challenge of Relapse and Recurrence . . . . . . . . 8045. Sources of Treatment Response Variability in Old-Age Depression: Why Do Only Some Patients

Get Well or Stay Well? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8045.1 Biological Predictors and Dimensions of Treatment Response Variability . . . . . . . . . . . . . . . . . . . 8045.2 Clinical Predictors and Dimensions of Treatment Response Variability . . . . . . . . . . . . . . . . . . . . . 8055.3 Intrapersonal and Environmental Predictors of Treatment Resistance . . . . . . . . . . . . . . . . . . . . . . 807

6. Addressing ‘Pseudo Treatment Resistance’: Promoting Adherence . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8087. Treatment Strategies: Switching versus Augmentation of Pharmacotherapy . . . . . . . . . . . . . . . . . . . . 808

7.1 Augmentation as a Strategy for Difficult-to-Treat Depression in Old Age . . . . . . . . . . . . . . . . . . . 8097.2 Switching as a Strategy for Difficult-to-Treat Depression in Old Age . . . . . . . . . . . . . . . . . . . . . . . . 8097.3 Electroconvulsive Therapy: A Key Treatment in Difficult-to-Treat Depression . . . . . . . . . . . . . . . . 811

8. Conclusion: ‘Stay the Course’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 811

In general, the pharmacological treatment of non-psychotic major depressiveAbstractdisorder in old age is only partially successful, with only approximately 50% ofolder depressed adults improving with initial antidepressant monotherapy. Manyfactors may predict a more difficult-to-treat depression, including coexistinganxiety, low self-esteem, poor sleep and a high coexisting medical burden. Beingaware of these and other predictors of a difficult-to-treat depression gives theclinician more reasonable expectations about a patient’s likely treatment course. Ifan initial antidepressant trial fails, the clinician has two pharmacological options:switch or augment/combine antidepressant therapies. About 50% of patients whodo not improve after initial antidepressant therapy will respond to either strategy.

802 Driscoll et al.

Switching has several advantages including fewer adverse effects, improvedtreatment adherence and reduced expense. However, as a general guideline, ifpatients are partial responders at 6 weeks, they will likely be full responders by 12weeks. Thus, changing medication is not indicated in this context. However, ifpatients are partial responders at 12 weeks, switching to a new agent is advised. Ifthe clinician treats vigorously and if the patient and clinician persevere, up to 90%of older depressed patients will respond to pharmacological treatment. Further-more, electroconvulsive therapy is a safe and effective non-pharmacologicalstrategy for non-psychotic major depression that fails to respond to pharmacother-apy. Getting well and staying well is the goal; thus, clinicians should treat toremission, not merely to response. Subsequently, maintenance treatment with thesame regimen that has been successful in relieving the depression stronglyimproves the patient’s chances of remaining depression free.

1. Challenges of Partial and to antidepressant therapy is a substantial publicNon-Response in Late-Life health issue because 50% of patients do not initiallyNon-Psychotic Depression respond to treatment. Once response is achieved,

keeping patients well (i.e. maintaining a durableresponse) is an ongoing challenge. Reynolds et al.[6]In the face of increasing numbers of older adults,recently demonstrated that approximately 60% offinding effective pharmacological strategies forcommunity-dwelling older adults with MDD, in-treating late-life, non-psychotic major depressivecluding those in their first lifetime episodes, becamedisorder (MDD) has become a public health priority.depressed again within 2 years unless they wereMDD in older adults is prevalent, amplifies disabili-maintained on antidepressant pharmacotherapy withty, hastens cognitive and functional decline, in-paroxetine. Compared with placebo, antidepressantcreases the risk of hospitalisation, diminishes quali-pharmacotherapy reduced the relative risk of recur-ty of life and burdens caregivers. Perhaps of gravestrence over 2 years by 60% (number needed to treat =concern is the increase in mortality from both asso-4).ciated medical co-morbidity and suicide.[1] Partially

treated MDD usually follows a relapsing, recurrent The OADIG (Old Age Depression Interestcourse.[2] Group) study was among the first placebo-con-

Clinicians need strategies to treat MDD, which trolled studies of depression prophylaxis in olderresponds only partially, if at all, to first-line pharma- adults.[7] This study found a 2.5-fold reduction incological treatments. In general, about 40–50%[3,4] relapse rates for patients prescribed dosulepinof older adults with non-psychotic MDD respond (dothiepin) 75 mg/day. In addition, only 30% ofsatisfactorily to the first prescribed antidepressant patients who received dosulepin relapsed over amedication. Response usually occurs within a period 2-year period. The Maintenance Therapies in Recur-of 3–4 months.[5] Response rates of about 50% have rent Depression study examined the use of nor-been reported in large-scale effectiveness studies, in triptyline for prevention of relapse among olderparticular the PROSPECT (Prevention of Suicide in adults with recurrent major depression.[8] This studyPrimary Care Elderly: Collaborative Trial)[3] and found that even when nortriptyline was prescribedIMPACT[4] studies. Slow, partial and non-response for at least 3 years after remission, 43% of patients

© 2007 Adis Data Information BV. All rights reserved. Drugs Aging 2007; 24 (10)

Managing Partial and Non-Response in Old-Age Depression 803

still experienced a recurrence. These results indicate sources bearing upon difficult-to-treat MDD in oldthat maintenance pharmacotherapy is critical to pre- age are also included. We acknowledge that ourvent recurrence but that there are still many patients review is not exhaustive, but believe that most of thewith a variable treatment response. clinically relevant data have been cited.

Treatment resistance or, more generally, treat- As described in section 1, we recently publishedment response variability, comprises several param- a systematic review of short-term antidepressanteters including: (i) rate of response, (ii) time to treatment response variability.[5] The data on long-symptom resolution, and (iii) response durability. term treatment response variability are not as exten-Whyte et al.[9] showed that, in general, rates of sive, and most of the work in this area has beenresponse appear to be similar for mid- and late-life conducted under the auspices of the Pittsburgh stud-MDD, although a few studies have noted differ- ies of maintenance treatment in depressed olderences.[5] For example, data from Reynolds et al.[10] adults.[6,8]

suggest that depressed older adults both respondslower and are more likely to experience relapse and 3. Short-Term Treatment:recurrence than middle-aged adults. Achieving Response

In this article, we focus primarily on pharmaco-Whyte et al.[5] reported that the speed of responselogical treatments (rather than psychosocial inter-

to antidepressant treatment in older (≥60 years ofventions) for non-psychotic, difficult-to-treat MDD.age) versus mid-life patients appears to beIn particular, we focus on the rate, speed and dura-equivalent. In their study, Alexopoulos et al.[12] sup-bility of response, remission and recovery from de-ported this observation of similar rates of responsepression in old age.[11] We also describe thebetween older and younger persons with MDD.psychosocial and biological characteristics that pre-These findings contradict the common clinical ob-dict treatment response. To conclude the discussionservation that older people with depression are slow-of pharmacological therapies, we discuss the currenter to respond to therapy than patients in mid-life.evidence for augmentation and switching treatmentWhyte et al.[5] suggested that in some instances, astrategies for older adults who either do not responddelayed antidepressant response may result fromto or who are only partial responders to first-linecautious titration of antidepressants because of aselective serotonin reuptake inhibitor (SSRI)desire to avoid adverse events. Whyte et al.[5] alsopharmacotherapy. We also briefly discuss the role ofsuggested that older adults with MDD who are treat-electroconvulsive therapy (ECT) as a non-pharma-ed as vigorously as younger patients may achievecological intervention for the elderly patient withsimilar response times. However, this approach isMDD.not without an increased risk of particular adverseevents in older adults such as falls and confusion. A2. Selection of Studiesbalance between achieving minimal response time,which may also help promote treatment adherence,Over the past 2 decades at the University ofand avoiding adverse events through an excessivelyPittsburgh (Pittsburgh, PA, USA), the authors haverapid escalation of antidepressant dose must deter-conducted a series of studies bearing upon short-mine the vigour with which older patients are treat-and long-term treatment response variability in old-ed.age, non-psychotic major depression. The results of

these studies are summarised in this review. Rele- Gildengers et al.[13] examined the relationshipvant reports from other groups that are primary data between age and both course of treatment response


804 Driscoll et al.

and rate of response. These investigators combined life populations with MDD. Klysner et al.[16] report-data across three studies in which a total of 323 ed that recurrence occurred less frequently withsubjects received antidepressant treatment. Subjects citalopram compared with placebo (32% vs 67%,were grouped into ‘young-old’ (59–69 years of age), respectively), while Wilson et al.[17] found no differ-‘middle-old’ (70–75 years) and ‘older-old’ (76–99 ence between sertraline and placebo in reducing theyears). Older-old patients had similar time to and risk of recurrence. In a more recent maintenancerates of response as the other two age groups, with therapy trial, Reynolds et al.[6] found that in patientsan overall response rate of 70% for all three age >70 years of age, 2-year rates of recurrence of MDDgroups. However, long-term treatment response were lower in those receiving paroxetine (35–37%)among the age groups may vary, with the very old than in those who did not receive pharmacotherapy(76–99 years) having a less durable response.[14] A (58–68%). Thus, it appears that in addition to thesimilar observation was reported in a study compar- importance of short-term pharmacotherapy dis-ing response rates, temporal course of response to cussed in section 3, long-term maintenance strate-acute treatment and relapse rates in elderly (≥60 gies should be implemented to reduce recurrence ofyears old) versus mid-life patients with MDD.[10] MDD in late-life patients, including those in theirThis study reported that elderly patients benefited first episodes.[6]

from antidepressants as much as but more slowly5. Sources of Treatment Responsethan mid-life patients; however, the course of recov-Variability in Old-Age Depression: Whyery in late-life MDD had a higher rate of relapseDo Only Some Patients Get Well or(15.5% vs 6.7%, respectively) during continuationStay Well?treatment.

Little et al.[15] found that only 11.9% of depressed Identifying factors that influence treatment re-elderly patients (mean age 67.6 years) did not expe- sponse variability is important for guiding both re-rience remission of MDD after several sequential search and clinical practice (figure 1).[18] Potentialtrials of augmentation pharmacotherapy. They con- predictors of such variability can be grouped intocluded that the rate of treatment resistance among several domains: biological, clinical, intrapersonaladults of this age group treated at a university tertia- and environmental. In figure 1, the predictors arery care setting is low if patients persist in sequential nested and, in essence, proceed from features mosttreatment strategies. Older adults with MDD, both integral to the person (his or her biology) to featuressingle episode and recurrent, require vigilance dur- that are environmental.ing maintenance pharmacotherapy to reduce theirincreased risk of recurrence. 5.1 Biological Predictors and Dimensions of

Treatment Response Variability4. Maintenance and Continuation

Certain biological measures predict treatment re-Treatment: The Challenge of Relapsesponse variability such as genetic and brain structur-and Recurrenceal changes. Pollock et al.[19] found that the presence

Compared to the number of maintenance efficacy of a homozygous or heterozygous genotype for thetrials of SSRI and non-tricyclic antidepressant s allele of the serotonin transporter gene promoterpharmacotherapy in non-elderly adult populations, region polymorphism (serotonin transporter lengthrelatively few have examined maintenance efficacy, polymorphism repeat [5-HTTLPR]) predicted acharacterised by the absence of recurrence, in late- slower response to short-term paroxetine treatment,



Biological• Nonpsychiatric physical• illness• Gene polymorphisms

Clinical• Symptom severity• Lifetime age of onset• Co-morbid anxiety• Cognitive impairment

Psychosocial −intrapersonal• Demographics• Personality disorder• Traits and dispositions

Psychosocial −environmental• Social supports• Perceived chronic stress• Life events/acute stress• Physical environment

Thedepressedolder adult

Biological

Clinical

Psychosocial −intrapersonal

Psychosocial −environmental

Fig. 1. Nested potential predictors of treatment response in late-life depression.

but not to nortriptyline. Some studies have also at baseline and older age at first lifetime depressiveshown that neuroradiological signs may predict episode (see later in this section) all predicted atreatment response variability. Hickie et al.[20] found more rapid and durable treatment response. Dewin a retrospective cohort study that severity of white et al.[23] both confirmed certain predictors of treat-matter hyperintensities on magnetic resonance ment response variability and defined specific path-imaging (MRI) predicted a poorer response to ways that treatment response may follow.antidepressant treatment. Baldwin et al.[21] also Gildengers et al.[24] found that baseline depres-found that MRI lesions affect treatment response sion severity scores were a significant predictor ofvariability. In a further analysis of these subjects, response trajectory. Higher initial scores predictedPatankar et al.[22] found that increased Virchow- slower response. Flint and Rifat[25] examined time toRobins dilatation, which is a pathological marker response as a predictor of outcome in a 4-year open-consistent with small vessel disease of the brain, label study. A shorter time to recurrence was pre-predicted a poor response to antidepressant dicted by a longer time to response. In other words,monotherapy. getting patients well quickly was associated with

keeping them well longer.5.2 Clinical Predictors and Dimensions of

Medical burden also affects treatment response.Treatment Response Variability

Reynolds et al.[6] recently observed evidence of themoderating effect of the number and severity ofDew et al.[23] examined how various predictorscoexisting medical illnesses on long-term treatmentmay influence trajectories or pathways to recoveryoutcome in late-life MDD. Thus, increased medicalduring 18 weeks of open-label treatment with nor-burden foretells a more brittle treatment course dur-triptyline and interpersonal psychotherapy. Fouring maintenance pharmacotherapy.treatment response patterns were observed: (i) rapid,

sustained improvement; (ii) delayed but sustained Age at onset of the major depressive episode andimprovement; (iii) partial or mixed response; or past history of episodes also predict treatment re-(iv) no response. A less severe depressive episode, sponse. Driscoll et al.[26] characterised the neuropsy-less disruption of EEG sleep architecture measured chological, clinical characteristics and treatment


806 Driscoll et al.

outcomes of patients with (i) early-onset (<60 years likely to require drug augmentation compared withpatients with MDD and less persistent suicidality.of age) recurrent MDD, (ii) late-onset (≥60 years of

age) recurrent MDD or (iii) late-onset (≥60 years of The PROSPECT study[3] examined the reductionage) single-episode MDD. The groups did not differ in suicidal ideation in older depressed patients within response, remission or relapse rates. However, major depression after implementation of treatmentpatients with late-onset, recurrent depression took guidelines for depression care management. Theselonger to respond than those with late-onset, single- guidelines included SSRI antidepressant pharma-episode depression (12 vs 8 weeks, respectively). cotherapy for most participants and interpersonalPatients with recurrent depression had a higher like- psychotherapy in about 30% of participants. Thelihood of requiring at least one augmentation agent comparison intervention was usual antidepressantto achieve stabilisation. These results suggest that pharmacotherapy provided by primary care physi-recurrent episodes, particularly with late age of on- cians. Depression care management accelerated theset, may predict a harder-to-treat depression. Thus, speed of clinical improvement, especially with re-age has been observed to affect treatment resistance. spect to decline in suicidal ideation, and resulted in

greater rates of response and remission. In short,Suicidality or suicidal ideation appears to be aolder depressed adults who were treated accordingpredictor of treatment response variability. Szantoto the depression care management guidelines hadet al.[27] found that older patients with suicidal idea-more depression-free days and less suicidal ideationtion had a slower response to antidepressant treat-than patients who received usual care.ment. Older adults with suicidal ideation were more

likely to both require drug augmentation and to have Up to 65% of older depressed patients also havehigher rates of relapse during continuation treat- symptoms of anxiety that may affect treatment re-ment. sponse.[31] High pretreatment anxiety has been

shown to predict both decreased rates of re-In a second analysis of the relationship betweensponse[23,32] and a longer time to achieve both re-suicidal ideation and treatment response variability,sponse and remission.[23,33-35] Saghafi et al.[36] foundSzanto et al.[28] classified suicidality risk, accordingthat greater anxiety predicted a poorer response toto the suicide probe on the Hamilton Depressionshort-term (6-week) antidepressant treatment. KarpRating Scale (HDRS),[29] as low, medium or high. Aet al.[37] also reported that persistent anxiety in-statistically significant difference in response ratecreased the likelihood of partial (as opposed to full)was found among the three groups. After 12 weeksresponse, and increased the risk for earlier relapseof treatment, 85% of low-risk patients, 76.9% ofand recurrence. Furthermore, clinical experience hasmoderate-risk patients and 67.4% of high-risk pa-shown that the presence of co-morbid anxiety symp-tients had responded. The median time to responsetoms may also affect initiation of treatment andwas longer in the high-risk (6 weeks) and moderate-overall adherence since anxious patients often fearrisk groups (5 weeks) than in the low-risk group (3and anticipate adverse effects of prescribed antide-weeks). Based on these studies, it appears that sui-pressants.[38]

cidal ideation in adults with MDD predicts a moredifficult-to-treat depression. In addition, individuals More recently, Andreescu et al.[39] showed thatwith suicidal ideation are more likely to require high baseline anxiety increased both the risk of non-pharmacotherapy augmentation to achieve response. response and the risk of recurrence during mainte-Recently, Szanto et al.[30] reported that older adults nance treatment. Notably, adding lorazepam towith MDD and persistent suicidal ideation are more paroxetine pharmacotherapy in patients with higher



baseline anxiety did not improve depression treat- Saghafi et al.[36] found that race differed significant-ment outcomes. This study suggests there is a criti- ly between partial and non-responders. Older Afri-cal need to investigate other pharmacological solu- can Americans were less likely to achieve bothtions for treating depression with co-existing anxie- response and complete remission than their Europe-ty. One such avenue of inquiry is the adjunctive use an American counterparts. Given the increasedof an atypical antipsychotic medication, such as psychosocial and economic stressors African Amer-olanzapine or aripiprazole. Based on preliminary icans experience compared with Whites,[45] thesedata from Adson et al.[40] in younger populations, findings suggest that this vulnerable population ofour group is conducting a pilot study of the adjunc- older African Americans with MDD requires vigi-tive use of open-label aripiprazole (2.5–15 mg/day) lant treatment and follow-up to ensure adequatenested in a study of late-life maintenance antidepres- adherence and treatment outcomes.sant pharmacotherapy. Preliminary data indicate Studies of the relationship between response tothat some patients with depression and co-existing treatment and other demographic variables such asanxiety symptoms that have not subsided with socioeconomic status and education have yieldedantidepressant monotherapy and/or addition of lo- conflicting results.[46-48] Cohen et al.[49] showed thatrazepam have fewer anxious symptoms when low income predicted both worse response rates toaripiprazole is added and titrated to effect. antidepressant treatment and a greater persistence of

Some types of cognitive impairment may predict suicidal ideation. That study did not show educationa more difficult-to-treat depression. Alexopoulos to be a significant moderator. In contrast, Saghafiet al.[33,41] and Kalayam and Alexopoulos[42] found et al.[36] did not find that socioeconomic status pre-that executive dysfunction predicted persistent de- dicted a poor response to antidepressant monother-pressive symptoms and heightened risks of MDD apy with escitalopram. These conflicting reportsrelapse and recurrence despite antidepressant phar- about the association between socioeconomic statusmacotherapy. Executive dysfunction in late life may and treatment outcomes suggest that other moderat-arise from cerebrovascular disease. Although But- ing variables such as coping skills, problem-solvingters et al.[43] were not able to replicate the observa- abilities and tangible social support may be impor-tion that executive impairments predict poor treat- tant.ment outcomes, this area requires further study be-

Bosworth et al.[50] reported that greater impair-cause the degree of cognitive impairment may bement in activities of daily living and decreases inmodifiable.[43]

perceived social support predicted failure to remitafter 12 months of antidepressant pharmacotherapy.5.3 Intrapersonal and EnvironmentalExamining other psychosocial predictors of treat-Predictors of Treatment Resistancement response variability, Saghafi et al.[36] foundthat lower self-esteem predicted a poorer response toThere is evidence that some demographic vari-short-term (6-week) antidepressant treatment. Lenzeables have an effect on treatment resistance whileet al.[51] reported that lower self-perceived healthother variables do not.[44] Gender has been examinedstatus among the elderly with depression predictedas a predictor of response to augmentation and hasdecreased response rates and higher attrition. Highernot been found to be reliably associated with treat-levels of active and chronic stressors predicted ament resistance.[12,32,44] Being ‘old-old’ (usually de-poorer response to antidepressant pharmacother-fined as ≥80 years) seems to predict a more brittle

long-term response to antidepressant treatment.[14] apy.[23] Thus, low self-esteem, poor self-perceived


808 Driscoll et al.

health, decreases in perceived social support and ties in the sequencing and planning of medicationhigh stress, four variables conceptually related to taking.MDD, appear to predict a poor response to antide- To promote treatment adherence, the clinicianpressant treatment. should consider the patient’s cultural and social

context when negotiating treatment decisions forPersonality disorders are frequently associateddepression. One key strategy is a psychoeducationalwith poor outcomes in the treatment of late-lifeapproach to enhancing adherence and increasingMDD.[44,52] Morse et al.[53] found that patients withpatient self-management of depression.[56] Lincluster C (anxious/inhibited/fearful) personality dis-et al.[56] adapted components of various psychother-orders took longer to respond to short-term treat-apies to improve attitudes toward antidepressantment and were more likely to experience relapseuse, increase confidence in managing adverse ef-during continuation or maintenance phases. Vigor-fects and promote self-management of depression.ous, persistent treatment during the acute phase withAttention during antidepressant medication initia-pharmacotherapy and psychotherapy may bringtion may promote treatment adherence, which mayabout response and remission in patients with clus-result in a better treatment outcome.ter C personality disorders.

7. Treatment Strategies: Switching versus6. Addressing ‘Pseudo Treatment Augmentation of PharmacotherapyResistance’: Promoting Adherence

The literature is inconclusive as to the clinicalutility, safety and efficacy of augmentation (combi-Most of the discussion so far has pertained tonation) and switching strategies for geriatric patientstreatment resistance and the factors associated withwith depression who partially respond to therapy.poor response despite a patient’s receipt of levels ofOur data suggest that both pharmacotherapy aug-treatment believed to be adequate. However, non-mentation and switching strategies may be clinicallyadherence to prescribed treatment also contributeshelpful, if monitored carefully. Augmentationto poor outcomes. Mulsant and Pollock[54] statedpharmacotherapy is often defined as the addition tothat non-adherence can give the appearance of treat-antidepressants of an agent that is not US FDAment resistance, a phenomenon they have calledapproved for the treatment of depression (e.g. lithi-‘pseudo treatment resistance’. Recently, Saghafium, liothyronine, stimulants).[57] Combinationet al.[36] observed that African Americans with MDDantidepressant pharmacotherapy has been defined aswere more than four times as likely to report missingthe dual prescribing of two antidepressant medica-doses of antidepressant medication than Europeantions with different mechanisms of action. In ourAmericans in a short-term treatment study. Thissynthesis of the literature as it pertains to olderfinding is consistent with the results of anotheradults, we include combination pharmacotherapystudy[55] suggesting that racial differences in atti-with augmentation pharmacotherapy.tudes and beliefs about antidepressant therapy may

impact upon the decision to adhere to recommended Whyte et al.[9] found that about half of patientstreatment. Moreover, although the relationship be- with MDD treated with either augmentation ortween executive dysfunction and poor treatment switching respond to treatment. This finding hasoutcomes may be mixed, a depressed older adult been recently replicated by Karp et al.[58] in a cohortwith cognitive impairment is also at risk for non- of 40 older adults resistant to aggressive treatmentintentional treatment non-adherence due to difficul- with escitalopram. Of this group, 50% met criteria



for a full treatment response after being switched to a cohort of 38 patients aged ≥60 years who receivedduloxetine and treated with an average dose of open-label maintenance treatment with either nor-93 µg/day. Cumulatively, if older patients stay the triptyline or phenelzine and adjunctive lithium, ifcourse, the overall response rate may eventually be necessary. These investigators reported that ten pa-as high as 80–85% if their treatment is altered in one tients (26.3%) had a recurrence despite augmenta-of these two fashions.[59] tion. Recurrence was predicted by higher anxiety

symptoms and a longer time to respond to initialAdding medications may multiply the risk oftreatment. Furthermore, Flint and Rifat[63] observedadverse effects via unforeseen pharmacodynamicthat non-response to first-line pharmacotherapy mayinteractions. We therefore believe that switchingpredict relapse and recurrence of remitted geriatricantidepressant medications may be as effective asdepression. The cumulative probability of relapse oradding a second medication and may reduce therecurrence was 67% for patients who responded toburden of falls and adverse events.[60] We also be-second-line treatment (phenelzine with or withoutlieve that it is appropriate to evaluate the efficacy oflithium) compared with 18% for patients who re-adding depression-specific psychotherapy to antide-sponded to first-line treatment (nortriptyline with orpressant medication for achieving partial to full re-without lithium). This difference, also supported bysponse.work by Reynolds et al.,[6] suggests that patientswho require a switch in adjunctive pharmacotherapy7.1 Augmentation as a Strategy formay have a more brittle, less stable course of main-Difficult-to-Treat Depression in Old Agetenance pharmacotherapy characterised by a higher

During acute treatment for late-life depression, risk of recurrence.up to 84% of individuals either do not respond totreatment or respond and then relapse. Ultimately, 7.2 Switching as a Strategy for20–30% of depressed elderly patients do not achieve Difficult-to-Treat Depression in Old Agefull recovery with antidepressant pharmacother-apy.[5,15,61] Augmentation pharmacotherapy is one In a new study of medication switching, Karpstrategy used in elderly patients with difficult-to- et al.[58] found that 50% of depressed elderly patientstreat MDD. For patients who do not respond to a not responding to escitalopram experienced sympto-first-line pharmacotherapy, use of augmentation matic improvement after being switched to duloxe-strategies has been associated with a response rate of tine. For patients who do not initially respond, it has50%.[9] Since most older adults with MDD either been shown that up to 50% of these non-respondersinitially do not respond to or relapse during antide- may respond after switching to a well chosen alter-pressant pharmacotherapy, examining predictors of native antidepressant.[9,59,64] Ultimately, if a clini-response to augmentation is important in the context cian-patient team ‘stays the course’ through three orof treatment resistance. four antidepressant trials, 80–90% of patients will

achieve response.[59]For example, in an examination of predictors ofresponse in 69 older adults who required drug aug- Mulsant et al.[65] published guidelines that werementation for MDD either because of non-response used to conduct the PROSPECT study of primaryor relapse, Dew et al.[62] reported that only clinically care treatment of late-life depression.[3] Thesesignificant anxiety and a higher medical burden guidelines directed non-responders (those who dopredicted a longer time to recovery during augmen- not respond within 6 weeks of treatment) to betation pharmacotherapy. Flint and Rifat[25] followed switched to a new agent, whereas partial responders


810 Driscoll et al.

should be treated for up to 12 weeks before a new vestigators reported that most patients who hadpharmacological monotherapy is tried. This recom- shown a partial improvement after 4 weeks of treat-mendation fits with the observation that older de- ment responded fully after at least 4 more weeks ofpressed patients do get better, but this often takes treatment. In contrast, fewer patients who respondedmore time and perseverance. poorly after 4 and up to 10 weeks of treatment

became full responders even after 8 additionalRegarding treatment duration, building on an ex-weeks of treatment. Thus, although many patientspert consensus from 2001,[66] we recommend that ifwill become full responders after 9–12 weeks ofan elderly patient who is not responding to treatmenttreatment, patients who are likely to show little to nois receiving a low dose of medication then the clini-

cian should wait 2–4 weeks and then increase the response can be reliably identified after only 4dose and extend the trial. If the patient has received weeks and up to 10 weeks of treatment. These latteran adequate dose of a medication and is still not patients are those most likely to benefit from anresponding, switching is advisable. Similarly, if the early change in treatment such as switching antide-patient is a partial responder, the clinician should pressants. In short, if, after about 4–6 weeks ofincrease the dose of medication and then wait 3–5 treatment, a patient has a poor response (i.e. is a non-weeks before switching. If the patient is receiving a responder), ‘staying the course’ is unlikely to im-high dose of antidepressant, longer initial trials are prove symptoms and an early switch is appropriate.recommended (3–6 weeks if no or little response is If, however, after a similar period, the patient is aobserved or 4–7 weeks if only a partial response is partial responder, then the clinician and patient areobserved). advised to ‘stay the course’.

Mulsant et al.[67] recently studied the optimal Many clinical factors influence the decision toduration for antidepressant treatment in elderly pa- augment or switch. Clinicians frequently cite scena-tients using a pooled analysis (figure 2). These in- rios in which augmentation is indicated, but no

current consensus guides the decision. The clinicalscenario frequently cited for use of augmentation orcombination occurs when a patient has had signifi-cant partial response to an antidepressant and theclinician wishes not to compromise that improve-ment by discontinuing the original antidepressant.For example, consider the patient who has a baselineHDRS 17-item score of 32 which falls to 12 after 12weeks of antidepressant monotherapy. Some physi-cians may be reluctant to stop the original antide-pressant and start a new unproven agent, for fear thatthe substantial clinical gain could be lost. In thissituation, some clinicians would choose to use aug-mentation or combination pharmacotherapy. How-ever, to our knowledge, no evidence supports thefear that clinical ground may be lost by switchingmedications in someone who has improved fromsevere MDD to a partial response. In this instructive

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70

Pro

porti

on c

lass

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1 2 3 4 5 6 7 8Additional weeks of treatment

Partial respondersNon-responders

Fig. 2. Proportion of partial and non-responders after 4–10 weeksof antidepressant treatment classified as full responders after addi-tional weeks of treatment. Partial responders were defined as pa-tients with Hamilton Depression Rating Scale (HDRS) scores of11–14 or HDRS ≤10 with <50% decrease from baseline after 4–10weeks of antidepressant treatment. Non-responders were definedas patients with HDRS scores ≥15 after 4–10 weeks of treatment.Full responders were defined as patients with HDRS scores of ≤10and 50% decrease from baseline (reproduced from Mulsantet al.,[67] with permission).



scenario, we recommend switching to achieve re-mission.

Yet another clinical scenario in which many cli-nicians believe that augmentation is appropriate oc-curs when several trials of pharmacologicalmonotherapy have failed to achieve a response. Inthis case, we agree that after exhausting all suitableagents for pharmacological monotherapy, a courseof augmentation or combination treatment should betried.

7.3 Electroconvulsive Therapy: A KeyTreatment in Difficult-to-Treat Depression

Although the main indication for ECT in late-lifeis psychotic depression, this treatment is also indi-cated for and well tolerated by older patients withtreatment-resistant, non-psychotic MDD. We men-tion ECT briefly here as a key non-pharmacologicalstrategy in treatment-resistant MDD.[68] Most stud-ies of ECT are in patients who have not responded to

Table I. Helping elderly depressed patients get better: clinicalconclusions

Treat to remission, not to response

Give patients and caregivers psychoeducation andcountermeasures for adverse effects to enhance treatmentadherence

If patients are partial responders at 4–6 weeks, they have areasonable chance of being full responders by 12 weeks. Thus,‘stay the course’: do not change medication

If patients are partial responders at 12 weeks, switch to a newagent

If patients are non-responders as early as 4 weeks and up to 10weeks, they are not likely to be full responders at 12 weeks.Switch medication

Switching is as effective as augmentation (about 50% respond)and is associated with fewer adverse effects. Adherence iseasier, and prescription costs are less

Electroconvulsive therapy is a key strategy for treatment-resistantolder age depression

Coexisting medical illness burden moderates long-term treatmentresponse: patients with a greater global medical burden willusually have a more difficult-to-treat depression

Coexisting symptoms of anxiety pose substantial risk for a slow,incomplete response during acute treatment and early recurrenceduring maintenance treatment. The optimal treatment for co-existing anxiety symptoms in old-age depression is unclear

Pay attention to residual symptoms of anxiety and poor sleep.These symptoms may indicate a more difficult-to-treat depression

antidepressant pharmacotherapy. In a 2-year retro-spective study of patients >75 years of age, Gormley

cian must also understand that even though a patientet al.[69] found that ECT is highly efficacious in

with MDD may get better initially, careful attentiondepressed non-psychotic patients, with treatment re-

must be given to maintenance treatment so that thesponses being seen as early as after one treatment. Inpatient can remain depression free. We provide a lista multisite prospective study of ECT, Tew et al.[68]

of clinical conclusions in table I to guide the clini-found that despite having more physical illnessescian in helping older depressed patients to get better.and cognitive impairment, even the oldest patients

In general, it appears that the strategies of aug-(>75 years of age) with severe MDD tolerated ECTmentation and switching are equally efficacious ifin a manner similar to that for younger patients andsteps are taken to maximise treatment adherence. Indemonstrated a similar or better acute response. It isour opinion, the clinician may do better by switchingalso important to note that even though a patient

may not respond after only one or two treatments, pharmacotherapy agents instead of selecting aug-ECT as a non-pharmacological treatment strategy mentation. Switching has several advantages, in-for late-life MDD should not be abandoned. cluding potential avoidance of adverse effects, im-

proved treatment adherence and reduced out-of-8. Conclusion: ‘Stay the Course’ pocket expense for additional medications.

Finally, the clinician and the patient should workThe difficult-to-treat older depressed patientas a team and be willing to persevere through per-presents many challenges to the clinician who musthaps several different pharmacotherapy trials to getunderstand the various factors that may predict athe patient well. ECT is reserved for patients whorocky or even prolonged treatment course. The clini-


812 Driscoll et al.

11. Frank E, Prien RF, Jarrett RB, et al. Conceptualization andrespond partially or not at all to vigorous antidepres-rationale for consensus definitions of terms in major depres-

sant pharmacotherapy. In brief, the clinician and sive disorder: remission, recovery, relapse, and recurrence.Arch Gen Psychiatry 1991; 48 (9): 851-5patient are advised to ‘stay the course’ if an elderly

12. Alexopoulos GS, Meyers BS, Young RC, et al. Recovery inindividual’s depression does not get better at first.geriatric depression. Arch Gen Psychiatry 1996; 53: 305-12

13. Gildengers AG, Houck PR, Mulsant BH, et al. Course and rateof antidepressant response in the very old. J Affect DisordAcknowledgements2002; 69 (1–3): 177-84

14. Reynolds CF, Frank E, Dew MA, et al. Treatment in 70+-year-Funding for the preparation of this review was obtainedolds with major depression: excellent short-term but brittlefrom the National Institute of Mental Health P30 MH071944,long-term response. Am J Geriatr Psychiatry 1999; 7 (1): 64-9

R01 MH43832, R01 MH37869, T32 MH19986 and KL215. Little JT, Reynolds CF, Dew MA, et al. How common isRR024154; the John A. Hartford Foundation; and the Univer-

resistance to treatment in recurrent, nonpsychotic geriatricsity of Pittsburgh Medical Center endowment in geriatric depression? Am J Psychiatry 1998; 155 (8): 1035-8psychiatry. Dr Karp has acted as an advisory board consultant 16. Klysner R, Bent-Hansen J, Hansen HL, et al. Efficacy ofto Eli Lilly and received medication supplies from Eli Lilly citalopram in the prevention of recurrent depression in elderlyfor an investigator-initiated trial. The other authors have no patients: placebo-controlled study of maintenance therapy. Br

J Psychiatry 2002; 19 (1): 29-35conflicts of interest that are directly related to the content of17. Wilson KC, Mottram PG, Ashworth L, et al. Older communitythis review.

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