Recent Developments in Antidepressant Therapy in Special Populations

July 1, 2004
Daniel Hayes, MD, MBA

Supplements and Featured Publications, Current Trends for the Management and Treatment of Depression, Volume 10, Issue 6 Suppl

Major depressive disorder (MDD) in the elderly,children, and patients with unstable angina or acutemyocardial infarction (MI) is a serious disorder. Inelderly patients, where major depression is oftenoverlooked and may have a significant impact onthe quality of life, the goal of therapy is full remission.Selective serotonin reuptake inhibitors (SSRIs)have the most favorable combination of efficacy andside-effect profile for the elderly with MDD, regardlessof the presence of medical comorbidities.Although the dual agent venlafaxine has been proposedas an alternative agent for older patients whoare either nonresponders or partial responders toSSRIs, the frail elderly may be particularly vulnerableto its side effects. Most elderly patients have arelapse of depression when antidepressants arestopped; depression subsides when antidepressantsare resumed. Because recent evidence suggests thatthe dosage of an antidepressant that achieves remissionin the elderly does not always protect againstrecurrence, in addition to long-term maintenance,consideration should be given to increased dosage.Patients with major depression and either unstableangina or acute MI should be identified and consideredfor antidepressant treatment. Findings from therecent Sertraline Anti-Depressant Heart AttackRandomized Trial suggest that SSRIs may haveantiplatelet and endothelium-protective propertiesthat may benefit patients with depression andcomorbid coronary artery disease and ischemicstroke. Concern regarding the safety of SSRIs in childrenhas prompted new studies. Evidence suggeststhat the risks of SSRIs, except for fluoxetine, mightoutweigh benefits in the treatment of depression inchildren and adolescents.

(Am J Manag Care. 2004;10:S179-S185)

Antidepressant Therapy in the ElderlyWith Major Depression

Major depressive disorder (MDD) in theelderly is an important public health problemthat will continue to challenge managedcare as the aging population grows. In additionto worsening mood and diminishingfeelings of self-worth, MDD impairs physical,social, and cognitive functioning. MDD isalso associated with increased rates of mortalityand suicide in the elderly.1,2 Overall,clinically significant depression affects upto 14% of the elderly population; between2% and 4% of the elderly have MDD and approximately10% have minor depression.3-5Clinically significant depression, which isoften long term or recurrent, is untreated inat least 60% of the elderly4 and is associatedwith increased utilization of medical services.However, approximately 36% of all nursinghome residents receive antidepressants.6

The class of antidepressants most widelyprescribed among the elderly is the selectiveserotonin reuptake inhibitors (SSRIs) (eg,citalopram, fluoxetine, paroxetine, and sertraline).Compared with the older tricyclicantidepressants, SSRIs are equally effectivebut cause significantly less orthostatic, cognitive,cardiovascular, and anticholinergic sideeffects. The SSRIs are categorized as "newer"antidepressants, along with dual-action serotonin-norepinephrine reuptake inhibitors (eg,mirtazapine and venlafaxine), reversibleinhibitors of monoamine oxidase A, and norepinephrinereuptake inhibitors. A structuredreview7 of 27 trials involving these newerantidepressants in depressed elderly patients(with mostly MDD) found that approximately50% of subjects receiving them had at least a50% improvement in depressive symptomscompared with an average placebo responserate of 30%.

Efficacy. Most recent trials comparing theefficacy of different SSRIs for MDD in theelderly have shown these agents to be equivalentin efficacy. For example, sertraline wasshown to have efficacy comparable with flu-oxetine for MDD in a 12-week, double-blind,randomized trial.8 A more recent large, double-blind, placebo-controlled trial showedsertraline to be effective and well toleratedby older adults with MDD. Also, the efficacyof sertraline appeared greater in patientswith more severe depressive symptoms.9 Inanother recent study, mirtazapine andparoxetine resulted in similar rates of remission.10 A comparison of the dual agent venlafaxineand nortriptyline found nosignificant differences in remission rates oftreated patients.11 A single-blind study suggestedthat nortriptyline confers a significantlyhigher remission rate compared withcitalopram.12

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Treating to Full Remittance. The goal oftreatment of MDD in the elderly should beremission rather than simple response.13Among 100 elderly (aged 60-88 years)patients with recurrent MDD who were randomizedto receive bupropion or paroxetinefor 6 weeks, improvements in quality of lifewere achieved with either agent. However,remitters showed significantly ( <.001)greater improvement than both partialresponders and nonresponders on variousmeasures.14

Antidepressant Therapy in ElderlyWith Depression and Medical Illness.More aggressive antidepressant drug therapymay be warranted in some elderly patientswith depression and medical comorbidities.Approximately 25% of patients aged 65 yearsand older with long-term medical illnesshave significant coexisting depression; about15% have MDD.15 Elderly patients with bothlong-term medical illness and depressionhave greater overall impairment in quality oflife16 and may fail to adhere to treatment upto 3 times more often than non-depressedpatients.17

Only a few recent studies have demonstratedthe safety and efficacy of SSRIsamong elderly patients with medical comorbidities.An analysis of the pooled results forthe sertraline treatment group drawn from 2prospective, randomized, double-blind studiesinvolving either sertraline versus fluoxetine18 or sertraline versus nortriptyline8provided preliminary evidence that sertralineis a safe, well-tolerated, and effectiveantidepressant in elderly patients sufferingfrom hypertension and other forms of vascularcomorbidity.19 A more recent, randomized,double-blind, placebo-controlled trialinvolving more than 750 patients aged 60years and older with MDD showed sertralineto be superior to placebo in reducing depressivesymptoms, regardless of the presence ofcomorbid medical illness, on all 3 primaryoutcome measures of the study. The drugwas safe and well tolerated by patients withor without medical illness.20 Interestingly,the degree of improvement correlated withpatient cardiac, cerebral, or peripheral vascularpathology. This finding is consistentwith that of another study comparing buspironeand imipramine where patients withcardiovascular illness were likely to havehigher antidepressant response rates.21 Arecent analysis of the Cochrane databaseshowed that the use of antidepressant medicationsin medically comorbid depressedpatients was associated with 3 times therecovery rate of patients taking placebo.22Another recent study suggested that longtermmaintenance with antidepressanttreatment did not adversely affect elderlypatients with a high degree of cerebrovascularrisk.23 In all, these findings offer reassuranceto clinicians of the safety, tolerability,and efficacy of sertraline and other SSRIs.

Partially Responsive, Nonresponsive,and Frail Patients. Because many elderlypatients with depression are either nonresponsiveor partially responsive to SSRIs,there continues to be interest in alternativeagents. A review of 3 double-blind comparisonsand 4 open-label studies24 involvingthe use of the dual-action serotonin norepinephrinereuptake inhibitor venlafaxine inolder patients concluded that venlafaxinewas safe and effective in elderly patientswith MDD. Subsequently, an expert consensuspanel on the treatment of depression inthe elderly proposed venlafaxine as both analternative first-line antidepressant forsevere depression and an agent for SSRInonresponders.25 However, in the largeststudy examined by the review, nearly 30% ofsubjects taking venlafaxine withdrewbecause of adverse events.26 Furthermore,evidence from a recent trial suggested thatthe frail elderly may be especially vulnerableto the side effects of venlafaxine. The 10-week randomized, double-blind study,which compared the efficacy and tolerabilityof venlafaxine and sertraline in the treatmentof depression among nursing homeresidents, found that venlafaxine was lesswell tolerated and, possibly, less safe thansertraline.26 Thus, some medications thatappear safe among the community elderlymay be less safe among the frail elderly.Consistent with this, in a small placebo-controlledtrial in very old patients with nonmajordepression in long-term care facilities,paroxetine (which was not significantly betterthan placebo) was associated with 2cases of delirium.27

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Prophylaxis Against Recurrence. Elderlypatients in remission from MDD have ahigh rate of recurrence after discontinuationof antidepressant medication. Several recentstudies provide evidence regarding optimallength of treatment and antidepressantdosage for prophylaxis against recurrence.Fava et al28 found that fluoxetine-treatedpatients who relapsed after switching toplacebo would most likely respond to reinitiatingfluoxetine. A recent well-designed 48-week, randomized, controlled trial providedgood evidence that maintenance therapywith the SSRI citalopram is more effectivethan placebo in reducing recurrence ofunipolar major depression in the elderly. At48 weeks, 32% of citalopram-treated patientshad relapsed compared with 67% of theplacebo group ( <.0001).29 A small, open-labelstudy in older patients showed thatmaintenance with either paroxetine or nortriptylinedemonstrated similar efficacy inrelapse prevention and time to relapse.30

Increasing the maintenance dosage hasbeen considered as a strategy to managerecurrence of MDD in the elderly. Increasingthe dosage of sertraline in a general adultpopulation already receiving the drugreduced the recurrence rate of depression.31Wilson et al32 found evidence that challengesthe assumption that the dosage of an antidepressantthat achieves remission in an olderpopulation protects against recurrence. In arandomized, double-blind, placebo-controlledcontinuation/maintenance study of100 weeks duration, sertraline at therapeuticdosages did not provide significant protectionagainst recurrent depression in olderpatients compared with placebo. The studyfound that extreme age appears to be associatedwith an increased risk of recurrence ofdepression for more than 2 years, which wasconsistent with a similar finding in anotherstudy33 for 3 years. The authors made 3specific recommendations for relapse prevention:practitioners should (1) beware ofthe particular vulnerability of older peoplewith depression and encourage an aggressiveand closely observed treatment plan,(2) promote long-term antidepressant maintenance,irrespective of the number of previousepisodes, and (3) consider increaseddosage.32

Antidepressants in Children andAdolescents With Major Depression

Safer and More Effective AntidepressantsNeeded. Safer and more effective antidepressantsare needed for depressedchildren and adolescents. Approximately 2%to 6% of children and adolescents suffer fromdepression,34,35 and suicide ranks third as themost common cause of death in youthsbetween 10 and 19 years of age.36 Tricyclicantidepressants are potentially toxic and aregenerally regarded as ineffective for childrenwith MDD; there is only marginal evidence fortheir use in the treatment of the disorder inadolescents.37 SSRIs, because of early evidencesuggesting that they might be moreeffective and better tolerated in young people,have experienced a steady increase in prescriptionrate. The most supportive publishedtrial of fluoxetine, the only SSRI approved forchildren, suggested that fluoxetine was superiorin both children and adolescents withMDD compared with placebo.38 However,this study suggested that fluoxetine improvedonly selected measures of clinicianratedimprovement and failed to show anincrease in rate of remission or recovery.39

SSRIs With Unfavorable Risk-BenefitProfiles. In 2003, results of several recentlarge, randomized, controlled trials causednew concern regarding the effectiveness andsafety of SSRIs in children. As a result, theUnited Kingdom's Medicines and Health-Care Products Regulatory Agency issued ageneral advisory that all antidepressants,except fluoxetine, had unacceptable risk-benefitprofiles for the treatment of MDD inchildren up to the age of 18 years.40Meanwhile, the US Food and Drug Administrationrecommended that paroxetine notbe used in children and adolescents for thetreatment of MDD.41

In view of growing concern about publicationbias and the fact that researchers wereboth withholding unfavorable trial data andunderreporting adverse events in trials ofSSRIs, Whittington et al42 conducted a metaanalysisof the risk-benefit profile of individualSSRIs in children using published andunpublished data from trials conductedbefore April 2003. The authors identified 5randomized, controlled trials evaluatingSSRI versus placebo in patients between theages of 5 and 18 years that were published ina peer-reviewed journal or were unpublishedand included in a review by the UnitedKingdom's Committee on Safety ofMedicines. The authors concluded that,except for fluoxetine, risks from SSRIs mightoutweigh benefits in the treatment ofdepression in children and adolescents. Forparoxetine, the authors found a publishedtrial43 and 2 unpublished trials44 suggestingthat paroxetine does not improve depressivesymptoms but appears to be associated withincreased risk of serious adverse events, suicidalideation, and/or suicide attempt. Twotrials of sertraline45 provided equivocal orweak evidence of its efficacy and suggested itmight contribute to increased suicidalideation. Unpublished trials of citalopramand venlafaxine44 showed that these agentshad unfavorable risk-benefit profiles.Because the drugs reviewed by the authorshad been recommended for use in childrenon the basis of very restricted published evidence,they concluded that there was anurgent need for evidence-based medicineguideline developers to have greater accessto unpublished full-trial reports.42

Treatment of Patients With Acute CoronarySyndrome and Major Depression

Depression and Risk of Sudden Deathin Acute Coronary Syndrome. Several studieshave shown that the presence of depressionin patients with acute coronary syndrome(ACS) (ie, unstable angina or acutemyocardial infarction [MI]) confers anapproximate 3-fold increased risk of death,depending on the severity of depression. Inaddition, patients who survive acute MI haveimpairment in quality of life and functioningcommensurate with the degree of depression.46,47 The prevalence of MDD in patientswith acute MI or ACS is 15% to 23% and evenhigher when milder forms of depression areconsidered.48 Therefore, there is great interestin the effect of antidepressant treatmenton the quality of life and the functioning ofpatients with acute MI and comorbid depression.However, published evidence that antidepressantdrugs are either safe or effectivein patients with acute MI has been lacking.Indeed, few patients with recent acute MI orunstable angina and comorbid depressionreceive antidepressant treatment.49

Safety, Tolerability, and Efficacy ofSSRIs. The SSRIs, with their favorable safety,tolerability, and efficacy, have been usedincreasingly to treat depression in the elderlyand may prove capable of reducingmorbidity and mortality associated withACS. Several studies have found sertralineto be effective in patients with MDD afteracute MI and in patients with hypertensionand other cardiovascular morbidity.19,20 In asmall study by Shapiro et al,50 no significantchanges in heart rate, blood pressure, cardiacconduction, coagulation measures, orleft ventricular ejection fraction (LVEF)were observed.

Interestingly, in the recent large sertralinetrial conducted by Sheikh et al,20 thedegree of improvement in depressive symptomsin elderly patients correlated with theirseverity of cardiac, cerebral, or peripheralvascular pathology. In 2 studies in patientswith MDD and documented ischemic heartdisease, paroxetine has been shown to havefavorable efficacy and tolerability.51,52

Persistent or Recurrent Depression inACS Should Be Treated. The SertralineAntidepressant Heart Attack RandomizedTrial (SADHART), which involved 369 outpatientswith MDD who had been hospitalized the previous month for ACS (MI, 74%;unstable angina, 26%), provided evidencethat sertraline is safe and more effectivethan placebo in treating recurrent depressionin this population.53 The randomized,double-blind, placebo-controlled trial alsoshowed that sertraline treatment was notassociated with significant changes in LVEFor any other measures of cardiovascularfunction. The authors concluded that, evenin the absence of evidence that antidepressanttreatment reduces risk in ACS, persistentor recurrent depression in ACS shouldbe identified and treated.53

Quality of Life. A separate analysis of theSADHART trial population54 found thattreatment with sertraline was associated withsignificantly greater improvement thanplacebo on most quality-of-life measures.The improvement at 6 months was substantial,but nonspecific, and occurred withboth sertraline and placebo for the subgroupof at-risk patients who had experienceddepression before hospitalization forACS. The analysis also found depressionafter acute MI to be associated with moresevere baseline impairments in quality oflife and functional status than previouslyreported in nondepressed post—acute MIpatients or in depressed patients withoutcoronary artery disease (CAD).54

SSRIs, Platelet Activation, and IncreasedRisk of Sudden Cardiac Death. One of thefactors that may contribute to the increasedrisk of sudden cardiac death among patientswith both ACS and MDD is increased plateletactivation.55 SSRIs are known to inhibitplatelet activity. In a SADHART substudy,treatment with sertraline in depressed post-ACS patients was associated with reductionsin platelet endothelial activation, despitewidespread coadministration of antiplateletregimens, including aspirin and clopidogrel.This study suggests that the antiplatelet andendothelium-protective properties of SSRIsmight benefit patients with depression andcomorbid CAD and ischemic stroke.56

Conclusion

In general, of the newer antidepressants,the SSRIs continue to offer the most favorablecombination of efficacy and side-effectprofile for the elderly with MDD, regardlessof the presence of medical comorbidities,and should be used to achieve full remission.Modification of dosage and duration of treatmentmay be appropriate in elderly who arefrail or those who are prone to recurrence ofMDD. Although antidepressant treatmenthas not been shown to reduce the risk conferredby MDD in ACS, persistent or recurrentdepression with ACS should beidentified and treated. Currently, except forfluoxetine, risks from SSRIs outweigh benefitsin the treatment of depression in childrenand adolescents.

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