Escitalopram Treatment of Depression in HIV and AIDS

Escitalopram Treatment of Depression in HumanImmunodeficiency Virus/Acquired Immunodeficiency Syndrome

A Randomized, Double-Blind, Placebo-Controlled Study

Jacqueline Hoare, MD, FCPsych, Mphil,* Paul Carey, PhD, John A. Joska, MMed, FCPsych,*Henri Carrara, MPH, Katherine Sorsdahl, PhD,* and Dan J. Stein, FCPsych, PhD*

Abstract: Depression can be a chronic and impairing illness in people withhuman immunodeficiency virus (HIV)/acquired immunodeficiency syn-drome. Large randomized studies of newer selective serotonin reuptake in-hibitors such as escitalopram in the treatment of depression in HIV, examiningcomparative treatment efficacy and safety, have yet to be done in HIV-positivepatients. This was a fixed-dose, placebo-controlled, randomized, double-blindstudy to investigate the efficacy of escitalopram in HIV-seropositive subjectswith Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,major depressive disorder. One hundred two participants were randomlyassigned to either 10 mg of escitalopram or placebo for 6 weeks. An analysisof covariance of the completers found that there was no advantage forescitalopram over placebo on the Montgomery-Asberg Depression RatingScale ( p = 0.93). Sixty-two percent responded to escitalopram and 59%responded to placebo on the Clinical Global Impression Scale. Given therelatively high placebo response, future trials in this area need to be selectivein participant recruitment and to be adequately powered.

Key Words: Randomized controlled study, depression, HIV

(J Nerv Ment Dis 2014;202: 133Y137)

Depression can be a chronic and impairing illness in people livingwith human immunodeficiency virus (HIV)/acquired immuno-deficiency syndrome (AIDS). Depression occurs in almost twice asmany people with HIV when compared with the general populationin the developed world (Ciesla and Roberts, 2001). In lower- andmiddle-income countries, indications are that depression affects up-ward of 30% of HIV clinic attendees (Olley et al., 2004).

In a South African primary care context, identification of de-pression was generally poor (Carey et al., 2003) and perhaps evenworse in clinics focused on chronic medical illnesses including HIV(Evans et al., 1996). Later in the illness, overlap with HIV symptoms(Jacobsberg and Perry, 1992) and side effects from antiretroviraltreatment in more advanced disease may serve to complicate diag-nosis (Kalichman et al., 2000). There is little doubt that a significantproportion of patients with comorbid depression and HIV gounrecognized and untreated.

Depression in HIV is associated with greater delays initiatingantiretroviral treatment (Fairfield et al., 1999) and poorer adherence

to antiretroviral medication (Gordillo et al., 1999). Depression isimportant not only because of its psychological impact but also be-cause of its impact on the course of HIV. Evidence suggests thatdepression accelerates HIV disease progression (Leserman et al.,1999) and is independently associated with increased HIV mortalityand a more rapid decline in CD4+ lymphocyte counts (Ickovics et al.,2001). Compliant selective serotonin reuptake inhibitor (SSRI) usehas been associated with improved antiretroviral adherence and lab-oratory parameters (Horberg et al., 2008). It is possible that early andeffective treatment of depression in HIV may significantly improvequality of life and that longer-term use may have an influence on HIVdisease progression and associated morbidity.

Expert consensus suggests that selective SSRIs are first-linetreatments of depression in HIV (Caballero and Nahata, 2004).SSRIs may be as effective as and better tolerated than tricyclic anti-depressants (TCAs) in HIV-positive adults (Caballero and Nahata,2004). However, published controlled studies in this area are limitedto trials with fluoxetine versus placebo (Rabkin et al., 1999) andparoxetine versus imipramine (Elliott et al., 1998), with comparableresponse rates as in depressed cohorts without HIV. A recent meta-analysis of the use of SSRIs for depression in HIV argued that thelack of data prevented conclusions being drawn on the most usefulSSRIs in this context (Ferrando and Freyberg, 2008). Because offluoxetines properties as an inhibitor of cytochrome P450 isoforms2D6 and 3A4 and its long half-life, interactions with antiretroviralsmay occur. Newer SSRIs such as citalopram and escitalopram offer atheoretically lower potential for drug-drug interactions, but large ran-domized studies examining comparative treatment efficacy and safetyhave yet to be done in HIV-positive patients. A recent meta-analysis of12 new-generation antidepressant drugs in non-HIV cohorts in thetreatment of depression found, for both efficacy and acceptability, infavor of escitalopram and sertraline (Cipriani et al., 2009).

Escitalopram, the most selective SSRI available (Owens et al.,2001), may offer a particular advantage for treating depression inHIV. Aside from the established efficacy of escitalopram in non-HIVdepression (Burke et al., 2002; Lepola et al., 2003; Wade et al.,2002), escitalopram mediates a more rapid and robust treatment re-sponse than its predecessor citalopram (Gorman et al., 2002) andhas only weak or negligible effects on hepatic enzymes crucial to themetabolism of most medicines including those frequently used inhighly active antiretroviral therapy (Brosen and Naranjo, 2001;Gutierrez et al., 2003; von Moltke et al., 2001). This drug-drug inter-action remains relevant in South Africa because patients are still pre-scribed protease inhibitors (PIs). The South African antiretroviralroll out programme consists of a nonnucleoside reverse transcriptaseinhibitor (NNRTI) based first-line regimen and a ritonavir-boostedprotease inhibitor (PI) containing second-line regimen. Ten milli-grams of escitalopram per day is effective and well tolerated in thetreatment of depression in primary care (Burke et al., 2002).

Therefore, the present study aimed to investigate the efficacyand tolerability of escitalopram for the treatment of Diagnostic and

ORIGINAL ARTICLE

The Journal of Nervous and Mental Disease & Volume 202, Number 2, February 2014 www.jonmd.com 133

*Department of Psychiatry and Mental Health, University of Cape Town, CapeTown, South Africa; Department of Psychiatry, Faculty of Health Sciences,Stellenbosch University, Tygerberg Hospital, Cape Town, South Africa; andSchool of Public Health and Family Medicine, University of Cape Town,Cape Town, South Africa.

Send reprint requests to Jacqueline Hoare, MD, FCPsych, Mphil, Department ofPsychiatry and Mental Health, University of Cape Town, Anzio Road Obser-vatory, 7925, Cape Town, South Africa. E-mail: [email protected].

Copyright * 2014 by Lippincott Williams & WilkinsISSN: 0022-3018/14/20202Y0133DOI: 10.1097/NMD.0000000000000082

Copyright 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV ),major depressive disorder (MDD) in people with stage III HIVinfection.

METHODSThis study was a fixed-dose, placebo-controlled, randomized,

double-blind study to investigate the efficacy of escitalopram in HIV-seropositive subjects with DSM-IV MDD. Patients meeting inclusionand exclusion criteria were recruited from primary and secondarylevel clinics and then referred to Tygerberg Hospital, University ofStellenbosch South Africa, to participate in this study. Participantselection was a semirandom, convenience sample of consecutivelyscreened patients attending primary care antiretroviral therapy clinicsin Tygerberg Hospital and in the community clinics. Protocol wasapproved by the ethics committee of the University of Stellenbosch,and the patients signed informed written consent.

ParticipantsEligible participants were HIV seropositive (World Health

Organization stage III); ranged in age from 18 to 60 years; and metcriteria for a DSM-IV diagnosis of a current major depressive episodewithout psychosis, according to the Mini-international neuropsychi-atric interview-plus neuropsychiatric interview. Exclusion criteriaincluded patients who currently or in the last 6 months have fulfilledcriteria for DSM-IV alcohol or substance abuse/dependence, lifetimehistory of bipolar disorder, history of schizophrenia, or other psy-chotic disorders or dementia; patients presenting at screening with ev-idence of mild cognitive impairment and who were unable to score 10or higher on the HIV Dementia Scale and 23 or higher on the Mini-Mental State Examination (MMSE); and patients with a positiveurine screen for any prohibited substance (including amphetamines,barbiturates, cocaine, marijuana, methadone, opiates, phencyclidine, orpropoxyphene) or medication (benzodiazepines) at the screening visit.

ProcedureThe participants received an initial screening and evaluation,

including a review of medical and psychiatric history. This first visitwas followed by 7 days (T3) of single-blind placebo to exclude earlyplacebo responders and to monitor compliance. Thereafter, the sub-jects were randomized to treatment of 10 mg per day of eitherescitalopram or matching placebo for the full 6 weeks of the study.

Clinical examination (including full systemic examination,weight, blood pressure, pulse, and electrocardiogram) and laboratorytests (full blood count, electrolytes, renal function, liver function,thyroid function tests, pregnancy screen, and urine drug screen) wereconducted at screening. HIV disease stage (CD4, CD8) was done atbaseline and at successful completion of the study as a final assess-ment, whereas efficacy measures were collected every week. Safetyand tolerability measures were done at weeks 1, 2, 4, and 6 by thestudy nurse. Adherence was monitored in dispensing packs weeklyand with patient report.

Measures

Primary Outcome MeasureMontgomery-Asberg depression rating scale

The 10-item MADRS (Montgomery and Asberg, 1979) iswidely used and validated for assessing symptom severity in depres-sion. It has been shown to be a reliable measure to detect depression inHIV-positive subjects (Cockram et al., 1999) and has been found torespond robustly to effective pharmacotherapy in a number of condi-tions with neurovegetative symptoms, including Parkinsons disease(with a preponderance of subcortical cognitive decline; Leentjens et al.,2003, 2000), headache (Walker et al., 1998), and cognitive impairment(Gabryelewicz et al., 2004).

Secondary Outcome MeasuresHospital anxiety and depression scale

The Hospital Anxiety and Depression Scale (Zigmond andSnaith, 1983) is a reliable and well-validated self-report measure ofdepressive and anxiety symptom severity in medically ill populationsincluding HIV (Savard et al., 1998).

Hamilton depression rating scaleThe Hamilton Depression Rating Scale (Hamilton, 1960) is an

observer-rated 17-item measure of depression severity that reliablydifferentiates depressed from nondepressed subjects in HIV disease(Cockram et al., 1999) and other medical illnesses (Leentjens et al.,2000) and has been widely used in treatment studies of depression inHIV (Elliott et al., 1998; Rabkin et al., 1999; Zisook et al., 1998).

Clinical global impression scale of severity and improvementThe Clinical Global Impression Scale of Severity (CGI-S) and

Improvement (CGI-I; Guy, 1976) is a well-validated, clinician-ratedglobal assessment of disease severity (CGI-S) and improvement.CGI responder status is defined as a week 6 score of 2 (much im-proved) or 1 (very much improved) in the global assessment of im-provement (CGI-I) from baseline.

Sheehan disability scaleThe Sheehan Disability Scale (SDS; Sheehan, 1983) is a

patient-rated three-item visual analog scale for assessing impairmentin the domains of work, family, and social life.

HIV dementia scaleThe HIV Dementia Scale (HDS; Berghuis et al., 1999; Power

et al., 1995) is a brief and reliable measure of global cognitivefunction that is reliably able to identify early cognitive decline of asubcortical pattern.

Mini-Mental State ExaminationThe MMSE (Folstein et al., 1975) is a widely used and vali-

dated screening tool for cognitive impairment that was used in ad-dition to the HDS. The MMSE is a reliable brief screening tool usedto identify cognitive decline of a cortical pattern. The pattern of HIV-associated brain loss may be changing from a subcortical to a corticaldisease among HIV-positive patients (Cohen et al., 2010). Assess-ment of cognitive functioning on all subjects at screening was designedto exclude significant cognitive impairment that may negatively influ-ence the ability to comply with the study protocol.

Blood was taken to measure CD4 and CD8 counts.

AnalysisAll analyses were conducted using the Statistical Package for

the Social Sciences and Stata version 11.1 (StataCorp LP, 4905Lakeway Dr, College Station, TX 77845). A sample size of 56 pa-tients per treatment group was required to detect a 3-point differenceon MADRS scores at week 6 between the treatment and placebogroups, with significance at 5% level, assuming a 20% dropout rate.An intention-to-treat analysis was not conducted because of the verylow dropout rate. The efficacy of escitalopram over placebo was testedusing an analysis of covariance (ANCOVA) model including thebaseline score as a covariate. CD4 counts were square root transformedto achieve a normal distribution, and all other outcome measures wereassessed to be normally distributed using the Shapiro-Wilks test. TheFriedmans test was conducted on theMMSE and the international HIVdementia scale (IHDS) because the data were not normally distribu-ted and could not be transformed to achieve a normal distribution.Treatment-emergent adverse events (hereafter referred to as adverseevents) were analyzed. The chi-square test was performed for the in-cidence of adverse events in the escitalopram group versus that in theplacebo group.

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RESULTSA total of 105 participants, predominantly women (86%),

participated in the study and were randomly assigned to either thetreatment or control groups. With three participants lost to follow-upin the first 2 weeks (in the treatment group), a total of 102 patientscompleted baseline and all weekly assessments (51 in the treatmentgroup and 51 in the control group). All participants included in thestudy were 100% adherent to treatment. The dropout rate was 2.9%.Reasons for loss to follow-up were unrelated to side effects, and allthree participants withdrew within the first 2 weeks of the first studyvisit. Both groups were well matched regarding the baseline demo-graphic characteristics and the mean group scores on the outcomemeasures used in the study, with the exception of the CGI severitymeasure, in which the mean for the treatment group (5.09) was sig-nificantly higher than that for the control group (4.74; Table 1).

The results of the ANCOVA models are presented in Table 2.The primary efficacy analysis showed an adjusted mean change inMADRS total score from baseline to week 6 of j14 points in theescitalopram group andj13 points in the placebo group. The treatmentdifference was not statistically significant ( p = 0.93). Given that theMADRS was the primary outcome of interest, we further exploredthis variable using cross-sectional time series regression analysis toaccount for changes during the six visits. The results of this analysis didnot alter the conclusion that there was no statistically significant dif-ference according to treatment group ( p = 0.2). TheMADRS improvedover time in both the placebo and escitalopram groups, p G 0.001(see Fig. 1). Similar findings were also reported for changes in SDS( p 9 0.001) and HDS ( p 9 0.001) scores in both groups.

In addition, after controlling for baseline scores, there was nosignificant effect of escitalopram on the remaining secondary out-come measures. Overall, 62% responded to escitalopram and 59%responded to placebo on the CGI. Furthermore, the proportion of theescitalopram-treated patients in complete remission (28%) was notstatistically significantly higher than that of the placebo-treated pa-tients at week 6 (35%; p = 0.47).

Treatment-emergent side effects were relatively uncommon, andthe only one that differed between the treatment groups was nausea and

vomiting. Nausea and vomiting was more frequently reported in thosein taking escitalopram than the placebo group ( p = 0.012).

DISCUSSIONThis study found no statistically significant advantage for

escitalopram over placebo in the treatment of depression in HIV. Ahigh placebo response (59%) was evident. There was also no sig-nificant effect of escitalopram on the remaining secondary outcomemeasures. Treatment-emergent side effects were relatively uncom-mon, with nausea and vomiting more frequently reported in thosetaking escitalopram than the placebo group. In terms of safety, thestudy did not find a negative effect of escitalopram on CD4 cellcounts. However CD4 cell counts did not decline significantly overtime, and no positive effects on CD4 cell count were observed.

High placebo response rates have been reported in a numberof SSRI double-blind randomized controlled trials in HIV. In a pre-vious randomized, double-blind, placebo-controlled prospective trialexamining the efficacy of fluoxetine in treating depression in HIV-positive subjects, Rabkin et al. (1999), in an intent-to-treat analysis,found the difference between the fluoxetine and placebo groups inimproving depression to be nonsignificant. The failure of these dif-ferences to be ultimately significant was attributed to an unusuallyhigh placebo response. Elliott et al. (1998), in a randomized, blinded,placebo-controlled prospective trial comparing the efficacy of anSSRI, paroxetine, versus a TCA, imipramine, showed that althoughboth paroxetine and imipramine were effective through week 8 of thestudy, paroxetine was not superior to placebo at week 12; this findingmay be explained by an unusually high placebo response at week 12.A range of factors may be contributing to the placebo response, in-cluding sex, empathy and compassion of the clinical staff, setting of thetrial, frequency of the visits, and severity of symptoms (Stein et al.,2006). Of note is that the study participants in this trial were receivingcare that was significantly better than treatment as usual. Inadequateservices exist for the diagnosis, treatment, and management of mentalhealth problems in many clinics specializing in treatment of peopleliving with HIV. It is also notable that attrition of 2.9% was lower thanthat reported in other studies of HIV-positive patients. It is our clinical

TABLE 1. Group Characteristics at Baseline

Escitalopram Control

Variable n n (%) n n (%) p

Sex 0.22Male 51 4 (7.8) 51 8 (15.7)Female 51 47 (92.2) 51 43 (84.3)

Age, median (range) 51 34 (23Y56) 51 34 (24Y54) 0.82Race 51 51 0.26Black 35 (68.6) 28 (54.9)White 1 (1.96) 0 (0)Colored 12 (23.53) 21 (41.2)Indian 1 (1.96) 0 (0)

MADRS, mean (SD) 51 31.73 (4.74) 51 30.11 (5.58) 0.12HAM-D, mean (SD) 51 21.33 (5.20) 51 19.64 (5.51) 0.11MMSE, median (range) 51 29 (23Y30) 50 29 (23Y30) 0.37IHDS, median (range) 51 11 (10Y12) 51 11.5 (10Y12) 0.55SDS total, mean (SD) 50 20.80 (6.27) 51 18.76 (6.86) 0.12CD4 count, median (range) 48 425.5 (144Y1072) 48 350.5 (3Y1144) 0.37CD8 count, mean (SD) 47 1278.64 (535.86) 47 1135.94 (526.69) 0.2CGI severity, mean (SD) 51 4.80 (0.80) 51 5.16 (0.73) 0.02*

*Significant difference at baseline.HAM-D indicates 17-item Hamilton Depression Rating Scale.

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impression that the excellent supportive care given by the study nurse tothe participants was crucial in retaining participants in the study;however, possibly, it also responsible for the high placebo response rate.If placebo responses in clinical trials are due to frequent patient eval-uation and increased attention, then high placebo response rates un-derscore the power of the expectancy effect created by the relationshipwith the trial team and the therapeutic context (Stein et al., 2006). Areviewof the placebo response in escitalopram placebo-controlled trialsfound that a higher placebo response rate was predicted by decreasedbaseline disorder severity (Stein et al., 2006).

Our study is noteworthy in so far as it is one of the firstconducted in a lower- and middle-income country that comprisespredominantly African women. The participants were recruited fromprimary and secondary level clinics specializing in treatment ofpeople living with HIV and were invited if they had a diagnosis ofdepression. Recent studies showed that HIV-positive women may bemore likely to be on antiretroviral therapy (antiretroviral therapy;Nattrass, 2006). For example, in South Africa, men who present forantiretroviral therapy are sicker on average than women, suggestingdelays by men in getting tested or care seeking once tested (Bekkeret al., 2006). A study of HIV-positive men in the Cape Town area foundthat additional barriers included the notion that clinics are places forwomen and HIV/AIDS is awomens issue (Kagee et al., 2011). In across-sectional study examining the correlates of depression in a publicsector antiretroviral program, most of the study participants were fe-male (75.7%; Pappin et al., 2012). Previous studies on depression inHIV have overrepresented gay/bisexual male participants and un-derrepresented female and African HIV-positive participants, pos-sibly because of the fact that most studies have been conducted inhigher-income countries. Factors that may contribute to depression

in this HIV-infected population include stigmatization, lack of socialsupport, and the death of a loved one from HIV/AIDS. Individualsmay therefore respond well to a supportive intervention of the kindprovided by a clinical research trial.

CONCLUSIONSFuture studies could focus on a longer treatment duration with

escitalopram or be more selective in participant recruitment. In thiscase, a more selective approach would be to include only severe/persistent MDD.

DISCLOSURESThis study was funded by Lundbeck. Lundbeck South Africa

(SA) is a subsidiary of H. Lundbeck A/S, an international, Danish,research-based pharmaceutical company focusing on the centralnervous system. Jacqueline Hoare is funded by the Discovery Foun-dation. Dan J. Stein is funded by the Medical Research Council ofSouth Africa (MRC). John A. Joska is funded by the National Re-search Foundation of South Africa.

The authors declare no conflict of interest.

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TABLE 2. ANCOVA of Follow-up Scores as a Function of Treatment Baseline Scores as Covariate

Placebo Escitalopram

Outcome nBaseline,Mean (SD) n

Follow-up,Mean (SD)

Change FromBaseline n

Baseline,Mean (SD) n

Follow-up,Mean (SD)

Change FromBaseline

TreatmentDiff (SE) p

MADRS 51 30.1 (5.6) 50 17.0 (10.5) j13.2 51 31.7 (4.7) 50 17.8 (9.5) j14 0.9 (2.0) 0.93HAM-D 51 19.6 (5.5) 50 11.8 (8.4) j8 51 21.3 (5.2) 48 12.3 (1.0) j9 1.1 (1.7) 0.98MMSEa 50 29 (23Y30) 43 29 (23Y30) 0 51 29 (23Y30) 44 29 (26Y30) 0 0.0 0.7IHDSa 51 11.5 (10Y12) 45 12 (9Y12) 0.5 51 11 (10Y12) 45 12 (10Y12) 1 0.5 0.86SDS total 51 18.8 (6.9) 49 13.9 (8.1) j4.6 50 20.8 (6.3) 51 12.84 (7.23) j8.1 3.5 (1.8) 0.3CD4 count 48 404.1 (218.5) 41 436.8 (210.6) 43.3b 48 454.3 (29.5) 37 433.6 (214.9) j10.7 54.0 (35.6) 0.2CD8 count 47 1135.9 (526.7) 41 1159.8 (486.1) j13c 47 1278.6 (535.9) 37 1205.8 (448.05) j54.6 41.5 (90.4) 0.96

aNot normally distributed; therefore, median and range were reported.bComplete data on 39 patients.cComplete data on 38 patients.diff indicates difference.

FIGURE 1. MADRS improvement over time in both placeboand treatment group.

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The Journal of Nervous and Mental Disease & Volume 202, Number 2, February 2014 Escitalopram in HIV Depression

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Escitalopram Treatment of Depression in HIV and AIDS